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QP912  .Ml  2  1906  On  the  mechanism  of 


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UNIVERSITY    OF    CALIFORNIA    PUBLICATIONS 


ON  THE  MECHANISM  OF  THE  PHYSIOLOGICAL 
ACTION  OF  THE  CATHARTICS 


BY 


JOHN  BRUCE  MacCALLUM 


Late  Assistant  Professor  of  Physiology  in  the  University  of  California 


BERKELEY 

THE  UNIVERSITY  PRESS 

1906 


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ON  THE  MECHANISM  OF  THE  PHYSIOLOGICAL 
ACTION  OF  THE  CATHARTICS 


BY 
JOHN  BRUCE  MacCALLUM 

Late  Assistant  Professor  of  Physiology  in  the  University  of  California 


BERKELEY 

THE  UNIVERSITY  PRESS 

1906 


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JOHN  BRUCE  MacCALLUM. 

Tlie  following  pamphlet  was  completed  only  a  few  days 
prior  to  the  death  of  the  author,  which  occurred  on  the 
sixth  of  April,  nineteen  hundred  and  six.  Through  his 
death  Physiology  was  robbed  of  one  of  its  most  brilliant 
young  investigators. 

John  Bruce  MacCallum  was  born  in  Dunnville,  Canada, 
on  the  eighth  day  of  June,  eighteen  hundred  and  seventy-six. 
Through  the  influence  of  his  father,  Dr.  G.  H.  MacCallum, 
now  Superintendent  of  the  State  Asylum  at  London,  On- 
tario, his  interest  in  the  natural  sciences  was  early  aroused 
and  during  his  college  career  at  the  University  of  Toronto 
as  much  of  his  time  as  possible  was  devoted  to  these  subjects, 
but  chiefly  to  biology.  After  his  graduation  in  1896  he 
entered  the  Medical  School  of  Johns  Hopkins  University. 
Under  the  influence  of  Professor  Mall  he  undertook  during 
his  first  medical  year  an  investigation  on  the  histogenesis 
of  the  cells  of  the  heart-muscle,  and  it  was  characteristic  of 
him  that  he  began  his  work  in  pathological  anatomy  also 
with  an  original  investigation.  During  the  third  year  of 
his  medical  course  he  again  prepared  several  anatomical 
papers  and  at  the  same  time  assumed  the  burden  of  the 
proof  reading  and  of  preparing  the  index  of  Barker's  book 
on  Neurology.  It  was  during  this  year,  1898-1899,  that  the 
first  symptoms  of  the  disease  appeared  which  was  to  cut 
short  the  life  of  this  talented,  indefatigable  worker.  From 
this  time  on  he  was  constantly  handicapped  in  his  work  by 
the  struggle  against  illness. 


After  his  graduation  in  medicine  in  nineteen  hundred 
he  returned  to  Baltimore  as  assistant  of  Professor  Mall.  In 
nineteen  hundred  and  one  he  went  to  Leipzig  to  work  in. 
the  laboratory  of  His,  but  his  old  enemy  again  interrupted 
his  work,  this  time  attacking  him  in  the  form  of  an  affection 
of  the  apex  of  the  lungs.  He  returned  home  as  soon  as  suffi- 
ciently recovered  to  bear  the  journey,  and  upon  the  advice 
of  Dr.  Osier  he  spent  the  winter  in  Jamaica.  Diiring  this 
period  he  translated  and  edited  Szymonowicz 's  histology' 
into  English. 

The  condition  of  his  health  made  it  impossible  for  him 
to  live  in  the  East  and  in  the  autumn  of  nineteen  hundred 
and  two  he  went  to  Denver,  "where  he  rented  an  office  and 
tried  to  practice.  He  abhorred  the  life,  though,  and  held 
in  contempt  the  charlatans  with  whom  he  came  in  contact. 
There  were  patients  and  he  made  enough  money  to  pay  his 
expenses  in  the  few  weeks  he  was  there,  but  the  repugnance 
to  that  kind  of  life  was  too  great,  and  he  abandoned  his 
practice.  They  had  made  him  teacher  of  anatomy  in  their 
medical  school,  in  charge  of  the  department,  I  believe.  The 
students  were  difficult  to  manage — their  ideals  being  far 
different  from  his.^ ' '  The  bright  spot  in  his  life  in  Denver 
was  his  association  with  Dr.  Sewall,  the  former  physiologist. 

Ha,ving  accepted  a  call  to  the  University  of  California,  I 
offered  Dr.  MacCallum  a  position  as  assistant  in  physiology, 
and  we  began  our  work  here  together.  During  the  first  and 
second  years  his  health  was  tolerably  good,  but  in  nineteen 
hundred  and  five  he  undertook  a  problem  on  immunity 
which  was  beyond  his  physical  strength  and  he  began  to  fail 
rapidly.  He  went  East  to  be  treated  by  Professor  Osier, 
returning  to  Berkeley  in  the  fall  of  the  same  year,  in  a  much 
weakened  condition,  but  if  he  realized  how  critical  was  his 
condition  he  betrayed  it  to  no  one.  He  was  cheerful  and 
apparently  hopeful.    As  he  was  not  able  to  exert  himself  in 

^  Quoted  from  a  letter  from  his  brother,  Professor  W.  G.  MacCal- 
lum, of  Johns  Hopkins  University,  to  whom  I  am  under  obligation  for 
the  data  given  in  this  sketch. 


experimental  work,  I  suggested  that  he  put  the  results  of  his 
experiments  done  at  Berkeley  into  book  form. 

The  present  volume  is  the  result  of  this  work,  the  last 
done  before  death  claimed  him.  It  has  been  published  with- 
out alteration.  The  preface  was  probably  written  two  days 
before  his  death,  which  came  suddenly- — as  he  had  always 
wished  that  it  might. 

MacCallum  belonged  to  that  type  of  scientists  whom  we 
may  designate  as  discoverers.  His  results  were  obtained 
quickly,  were  made  secure  beyond  doubt,  and  were  put  into 
such  shape  that  they  could  easily  be  demonstrated  by  him. 
But  as  is  also  common  in  the  case  of  discoverers,  his  publi- 
cations were  comparatively  brief.  This  may  make  it  at 
times  difficult  for  inexperienced  or  uncritical  workers  to 
repeat  his  experiments.  I  may  state,  however,  that  they 
belong  to  the  regular  class  exercises  of  the  medical  students 
in  our  laboratory.  Those  who  have  once  learned  how  to 
perform  them  can  always  count  upon  their  succeeding. 

In  his  work  as  well  as  in  his  life  he  was  a  calm  thinker, 
the  reverse  of  a  hustler.  He  conceived  his  experiments  in 
the  spirit  of  an  artist  and  the  realization  of  his  ideas  was 
the  poetry  his  work  put  into  his  life.  He  did  not  work  for 
outside  success,  nor  did  he  pose  as  a  benefactor  of  mankind. 

Those  who  have  known  him  well  feel  that  the  death  of 
John  Bruce  MacCallum  has  left  a  gap  which  will  never 
again  be  filled. 

Jacques  Loeb. 

Berkeley,  November  7,  1906. 


PUBLICATIONS  BY  JOHN  BRUCE  MacCALLUM. 

1.  Fresh-water  Cladocera. 

University  of  Toronto  Quarterly,  May,  1895. 

2.  On  the  Histology  and  Histogenesis  of  the  Heart  Muscle  Cell. 

Anatomischer  Anzeiger,  Bd.  XIII,  1897. 

3.  On  the  Pathology  of  Fragmentatio  Myocardii  and  Myocarditis 

Fibrosa. 

Johns  Hopkins  Hospital  Bulletin,  No.  89,  1898. 

4.  On  the  Histogenesis  of  the  Striated  Muscle  Fibre  and  the  Growth 

of  the  Human  Sartorius  Muscle. 

Johns  Hopkins  Hospital  Bulletin,  Nos.  90-91,  1898. 

5.  A  Contribution  to  the  Knowledge  of  the  Pathology  of  Fragmen- 

tation and  Segmentation  and  Fibrosis  of  the  Myocardium. 
Journal  of  Experimental  Medicine,  Vol.  IV,  1899. 

6.  Development  of  the  Pig's  Intestine. 

Johns  Hopkins  Hospital  Bulletin,  Vol.  XII,  1901. 

7.  Notes  on  the  Wolffian  Body  of  Higher  Mam^mals. 

American  Journal  of  Anatomy,  Vol.  I,  1902. 

8.  On  the  Muscular  Architecture  and  Growth  of  the  Ventricle  of 

the  Heart. 

Johns  Hopkins  Hospital  Eeports,  Vol.  IX,  1900. 
(Memorial  volume  to  Dr.  W.  H.  Welch  by  his  pupils.) 

9.  Text-book  of  Histology  and  Microscopic  Anatomy.     By  L.  Szy- 

monowicz.     Translated  and  edited  by  J.  B.  MacCallum.     Lea 
Bros.,  1902. 

10.  On  the  Mechanism  of  the  Action  of  Saline  Purgatives,  and  the 

Counteraction   of   their   Effect   by   Calcium.     (A   preliminary 
communication. ) 

University  of  California  Publications,  Physiology,  Vol.  I, 
1903. 

11.  On  the  Action  of  Saline  Purgatives  in  Eabbits  and  the  Counter- 

action of  their  Effect  by  Calcium.    (Second  communication.) 
American  Journal  of  Physiology,  Vol.  X,  1903. 
Also:   University  of  California  Publications,  Vol.  I,  1904. 


12.  On  the  Local  Application  of  Solutions  of  Saline  Purgatives  to 

the  Peritoneal  Surfaces  of  the  Intestine. 

American  Journal  of  Physiology,  Vol.  X,  1904. 

Also:   University  of  California  Publications,  Vol.  I,  1904. 

13.  On  the  Influence  of  Calcium  and  Barium  on  the  Flow  of  Urine. 

(A  preliminary  communication.) 
Ibid.,  1904. 

14.  The  Influence  of  Saline  Purgatives  on  Loops  of  Intestine  Ee- 

moved  from  the  Body. 
Ibid. 

15.  The  Secretion  of  Sugar  into  the  Intestine  Caused  by  Intravenous 

Saline  Infusions. 
Ibid. 

16.  The  Action  of  Cascara  Sagrada.    (A  preliminary  communication.) 

Ibid. 

17.  The  Influence  of  Calcium  and  Barium  on  the  Secretory  Activity 

of  the  Kidney.    (Second  communication.) 

University  of  California  Publications,  Physiology,  Vol.  II, 
1904.  Also  in  the  Journal  of  Experimental  Zoology, 
Vol.  I,  1904. 

18.  Ueber  die  Wirkung  der  Abfiihrmittel  und  die  Hemmung  ihrer 

Wirkung  durch  Calciumsalze. 

Pfliiger's  Archiv,  Bd.  104,  1904. 

19.  The  Action  on  the  Intestine  of  Solutions  Containing  two  Salts. 

University  of  California  Publications,  Vol.  II,  1905. 

20.  The  Action  of  Purgatives  in  a  Crustacean  (Sida  Crystallina). 

Ibid.,  1905. 

21.  On  the  Diuretic  Action  of  Certain  Haemolytics,  and  the  Action 

of  Calcium  in  Suppressing  Haemoglobinuria.    (A  preliminary 
communication. ) 
Ibid.,  1905. 

22.  The  Diuretic  Action  of  Certain  Haemolytics  and  the  Influence  of 

Calcium  and  Magnesium  in  Suppressing  the  Haemolysis.    (Sec- 
ond communication.) 
Ibid.,  1905. 

23.  The  Action  of  Pilocarpine  and  Atropin  on  the  Flow  of  Urine,  by 

John  Bruce  MacCallum. 
Ibid. 

24.  Factors  Influencing  Secretion. 

The  Journal  of  Biological  Chemistry,  Vol.  I,  1906. 


AUTHOE'S  PREFACE. 

The  following  pages  contain  an  account  of  a  long  series 
of  experiments  made  to  determine  the  action  of  saline  purg- 
atives. Many  of  the  results  have  been  separately  published 
in  various  scientific  journals,  and  they  are  now  gathered 
together  with  certain  new  material  in  an  attempt  to  give  as 
connected  and  complete  an  account  as  possible  of  the  action 
of  this  class  of  drugs. 

The  experiments  were  begun  at  the  suggestion  of  Pro- 
fessor Loeb,  to  whom  I  am  greatly  indebted  for  the  constant 
interest  which  he  has  taken  in  the  work,  and  whom  it  is  a 
pleasure  to  thank  for  many  helpful  suggestions. 


CONTENTS. 

PAGE 

Chapter  I. — Normal  Movements  and  Secretion  of  the  Intestine     1 

Chapter        II. — The   Subcutaneous  and   Intravenous   Injection   of 

Saline  Purgatives 9 

Chapter      III. — The  Local  Application  of  Saline  Solutions  to  the 

Peritoneal  Surfaces  of  the  Intestine  23 

Chapter       IV. — The  Production  of  Increased  Secretion  of  Fluid 

into  the  Intestine  by  the  Saline  Purgatives 29 

Chapter  V. — The  Inhibiting  Action  of  Calcium  and  Magnesium 
on  the  Movements  and  Secretion  of  the  In- 
testine     - - 38 

Chapter  VI. — The  Action  of  Saline  Solutions  on  Loops  of  Intes- 
tine Eemoved  from  the  Body 50 

Chapter  VII. — The  Action  on  the  Intestine  of  Solutions  Contain- 
ing Two  Salts 57 

Chapter  VIII. — The  Effect  on  the  Intestine  of  Intravenous  Saline 

Infusions 65 

Chapter      IX. — Mode  of  Action  of  the  Saline  Cathartics  74 

Chapter        X. — Possible  Therapeutic  Value  of  These  Experiments  83 

Chapter      XI. — The  Action  of  Purgatives  of  Vegetable  Origin 86 


CHAPTER  I. 
Normal  Movements  and  Secretion  of  the  Intestine. 

A.     Normal  Movements  of  the  Intestine. 

The  normal  movements  of  the  intestine  have  been  de- 
scribed by  many  observers,  and  in  these  descriptions  there 
is  a  fair  amount  of  uniformity.  Ludwig  and  his  pupils, 
Bayliss  and  Starling,  Magnus  and  others  have  studied  this 
subject  with  much  care.  In  such  a  complicated  organ  as 
the  intestine  there  are  many  sources  of  error,  and  differ- 
ences of  opinion  may  readily  arise  if  an  attempt  is  made  to 
analyze  too  closely  the  functions  of  the  various  tissues  mak- 
ing up  the  intestine,  to  decide  for  example  whether  the 
movements  are  of  nervous  origin  or  muscular,  or  whether 
the  secretion  is  dependent  primarily  on  the  blood  supply 
or  on  the  nervous  system.  For  our  purpose  it  will  be  suffi- 
cient to  regard  the  intestine  as  an  organ  composed  of  certain 
muscular  layers,  certain  nervous  plexuses  and  certain  glands 
— and  to  discuss  the  action  of  various  influences  not  on 
these  separate  tissues,  but  on  the  organ  as  a  whole,  holding 
in  mind  also  the  nervous  and  bloodvascular  connections  of 
the  organ. 

If  the  abdominal  cavity  of  a  dog,  cat,  or  rabbit  be  opened 
under  the  surface  of  m/6  NaCl  solution  or  Einger's  solu- 
tion at  body  temperature,  it  will  be  found  that  the  intestines 
are  not  entirely  at  rest.  According  to  local  conditions,  more 
or  less  active  movements  will  be  seen.  These  were  described 
by  Ludwig  and  others  as  consisting  of  two  kinds  of  motion, 


namely,  the  pendulum  movements,  and  peristaltic  move-^ 
ments. 

The  pendulum  movements  are  rhythmical,  and  consist 
of  a  regular  slight  swinging  of  the  loops  upon  one  another. 
Their  frequency  has  been  measured  by  Bayliss  and  Star- 
ling.^ According  to  these  observers,  each  contraction  and 
relaxation  lasts  5  to  6  seconds,  so  that  the  rhythm  consists 
of  10  to  12  beats  per  minute.  The  rhythm  is  however  not 
always  regular,  the  contents  of  the  loop  and  other  local  con- 
ditions exerting  an  influence.  The  cause  of  these  pendulum 
movements  is  not  perfectly  clear.  By  many  they  have  been 
ascribed  to  a  rhythmical  shortening  of  the  intestine,  i.e.,  a 
rhythmical  contraction  and  relaxation  of  the  longitudinal 
muscle  coat.  MalP  regards  them  as  arising  mainly  in  the 
circular  layer;  while  Bayliss  and  Starling  state  that  they 
are  due  to  simultaneous  contractions  of  the  circular  and 
longitudinal  coats. 

The  peristaltic  movements  consist  of  more  or  less  strong 
contractions  of  the  circular  coat  of  the  intestine,  varying 
from  a  slight  ring-like  contraction  which  passes  rapidly 
down  the  gut  to  a  violent  constriction  of  the  intestine  which 
obliterates  the  lumen  of  the  gut  and  passes  very  slowly  from 
above  downward.  The  slight  contractions  may  travel,  ac- 
cording to  Bayliss  and  Starling,  as  rapidly  as  2-5  cm.  per 
second,  while  the  more  violent  ones  move  not  more  than 
1/10  cm.  per  second.  According  to  Nothnagel,  Mall,  and 
others,  the  formation  of  these  peristaltic  waves  is  always 
due  to  a  local  stimulus,  usually  the  presence  of  a  bolus  of 
food.  The  intestine  contracts  immediately  above  the  point 
of  stimulation  and  the  mass  of  food  is  forced  downward. 
The  wave  of  contraction  follows  close  behind  the  bolus, 
while  for  some  distance  above  this  point  similar  waves  run 
downward  until  they  reach  the  mass  of  food.  The  gut  is 
usually  relaxed  below  the  bolus,  and  the  general  statement 

^  Journal  of  Physiology,  Vol.  XXIV,  1899,  p.  99. 
-  Johns  Hopkins  Hospital  Eeports^  Vol.  I,  1896. 


has  been  made  that  a  stimulation  at  any  point  causes  a  con- 
traction above  that  point  and  an  inhibition  below  it.  It  is 
generally  thought  that  Auerbach's  plexus  is  concerned  in 
the  propagation  of  the  peristaltic  wave  since  the  peristalsis 
takes  place  also  when  the  intestine  is  separated  from  the 
central  nervous  system,  and  does  not  occur  when  nicotine 
or  cocaine  is  given  to  paralyze  the  intrinsic  nerves  of  the 
intestine. 

In  addition  to  the  pendulum  and  the  peristaltic  move- 
ments, there  is  a  third  quite  distinct  motion  to  be  observed 
in  the  intestine.  The  normal  peristaltic  movements  are  very 
slow,  while  this  third  type,  called  by  Nothnagel ' '  Rollbewe- 
gung, ' '  consists  of  a  rapid  contraction  which  may  pass  from 
one  end  of  the  intestine  to  the  other  in  1  to  2  minutes.  The 
function  of  this  movement  is  thought  to  be  the  rapid  elimi- 
nation of  irritating  substances  from  the  intestine.  It  occurs 
irregularly  and  is  more  common  in  slight  pathological  con- 
ditions of  the  gut. 

It  is  generally  believed  that  the  normal  peristaltic  wave 
passes  only  from  above  downward,  and  never  in  the  reverse 
direction.  This  has  been  shown  in  many  ways.  MalP  re- 
moved a  certain  length  of  the  small  intestine  and  reversed 
it  so  that  the  end  which  had  originally  been  nearer  the 
stomach  was  now  in  the  position  formerly  occupied  by  the 
end  nearer  the  rectum.  The  food  would  not  pass  down  this 
part  of  the  intestine,  but  accumulated  above  it.  In  other 
words,  the  peristalsis  continued  as  it  was  before  the  loop 
was  removed,  the  wave  passing  in  the  reversed  loop  from 
below  upward.  A  further  illustration  of  the  same  thing  is 
seen  in  the  fact  that  in  an  isolated  loop  an  object  inserted 
in  the  gastric  end  of  the  loop  will  rapidly  be  passed  to  the 
other  end,  while  it  is  impossible  to  force  the  object  into  the 
rectal  end  because  of  the  peristaltic  waves  which  constantly 
expel  it.     Griitzner*  observed  that  the  intestinal  contents 

'  Loc.  cit. 

*Deutsch.  Med.  Wochenschr.,  XV,  1899. 


sometimes  move  backward  and  forward  in  the"  intestine, 
and  that  an  easily  recognizable  substance,  e.g.^  food  intro- 
duced into  the  rectum  in  enemata,  was  sometimes  to  be 
found  afterwards  in  the  stomach.  It  seems  further  from 
Cannon's^  study  of  the  cat's  intestine  by  means  of  th6 
Rontgen  rays  that  antiperistalsis  certainly  takes  place  in 
the  colon  of  this  animal.  In  the  transverse  and  ascending 
colon  antiperistaltic  waves  occur  at  the  rate  of  5-6  per 
minute.  No  antiperistalsis  was  observed  in  the  small  in- 
testine. 

Factors  which  normally  cause  or  influence  the  intestinal 
movements.  Although  there  has  been  some  divergence  of 
opinion  on  the  subject,  it  is  now  generally  held  that  anaemia 
of  the  intestine  causes  a  cessation  of  all  movements.  This 
has  been  shown  by  van  Braam-Houckgeest,®  Mall,'^  and 
others.  Clamping  of  the  aorta,  opening  of  the  heart,  etc., 
cause  all  movements  to  cease.  Hyperaemia  of  the  intestine 
on  the  other  hand  causes  active  movements  to  arise.  Any 
conditions  which  cause  a  venous  engorgement  of  the  intes- 
tine bring  about  intestinal  movements.  Bokai^  found  that 
COo  is  a  direct  stimulant  to  the  intestine,  and  that  the  move- 
ments may  be  stopped  by  the  application  of  oxygen.  Krause 
and  Heidenhain  first  noticed  that  when  an  animal's  breath- 
ing is  stopped  the  peristaltic  movements  of  the  intestine 
greatly  increase,  but  cease  when  the  breathing  is  recom- 
menced. 

The  influence  of  the  intestinal  contents  upon  the  move- 
ments of  the  gut  was  discussed  as  long  ago  as  1750  by 
Foelix.®,  Among  the  later  authors  to  treat  of  this  subject 
is  Bokai.  In  addition  to  indigestible  and  irritating  sub- 
stances taken  in  with  the  food,  there  are  certain  substances 
ordinarily  formed  in  the  intestine  by  decomposition  which 

'  Amer.  Journ.  Physiol.,  Vol.  VI,  1902. 
"Pfliiger's  ArcMv,  VI,  1872;  VIII,  1874. 
^  Johns  Hopkins  Hospital  Eeports,  I,  1896. 
^  Arch,  f .  exp.  Path.  u.  Pharm.,  Bd.  23-24. 
"  De  Motu  peristaltic,  intest.  Treviris,  1750. 


cause  peristaltic  movements.  Among  these  are  COo,  CH4, 
and  HgS.  All  of  these  gases  which  are  more  or  less  con- 
stantly formed  help  in  keeping  up  the  normal  movements 
of  the  intestine.  Certain  faecal  constituents  have  also  the 
same  effect.  Bokai  mentions  among  these  a  number  of  or- 
ganic acids — lactic,  succinic,  butyric,  formic,  propionic, 
acetic,  caproic,  and  caprylic  acids.  There  is  no  doubt  also 
that  the  salts  taken  in  with  the  food  exert  a  considerable 
influence. 

The  intestine  is  to  some  extent  also  under  the  influence 
of  extrinsic  nerves.  As  shown  by  Pfliiger,^"  the  splanchnic 
nerves  exert  an  inhibitory  action  on  the  intestine,  so  that 
their  section  causes  intestinal  movements  and  their  stimu- 
lation brings  about  a*  cessation  of  peristalsis.  This  has  been 
ascribed  by  some  authors  to  the  vasomotor  action  of  the 
nerves.  Concerning  the  action  of  the  vagus  there  has  been 
difference  of  results.  Many  experimenters  have  found  that 
stimulation  of  this  nerve  causes  contractions  of  the  intes- 
tine. Others  have  obtained  no  results.  If,  however,  the 
splanchnics  be  cut  and  the  inhibitory  impulses  abolished, 
stimulation  of  the  vagus  gives  constant  results  consisting  of 
a  slight  inhibitory  action  followed  by  an  increase  of  the 
rhythmical  contractions  of  the  intestine. 

B.     Normal  Secretion  Into  the  Intestine. 

It  is  probable  that  under  normal  conditions  a  fluid  is 
secreted  from  the  entire  length  of  the  intestine,  but  this 
fluid  undoubtedly  differs  somewhat  in  the  various  parts. 
The  duodenum  with  Brunner's  glands,  the  jejunum  and 
ileum  with  the  glands  of  Lieberkiihn  and  the  large  intestine 
in  which  there  is  a  preponderance  of  mucus  cells  may  be 
assumed  to  give  secretions  which  are  not  identical.  The 
methods  which  have  been  used  to  obtain  the  succus  entericus 


^''  tJber  das  Hemmungsnervensystem  f .  d.  peristal.  Bewegungen  d. 
Darmes,  Berlin,  1857. 


for  analysis  are  subject  to  criticism,  and  much  remains  to 
be  discovered  with  regard  both  to  the  mechanism  of  secre- 
tion and  the  nature  of  the  normally  secreted  fluid.  The 
most  fruitful  method  has  been  that  instituted  by  Thiry,^^ 
and  later  modified  by  Vella.^^  This  consists  of  the  establish- 
ment of  a  permanent  fistula  from  the  intestine  through  the 
skin  from  which  the  intestinal  juice  may  be  gathered  after 
complete  healing  has  taken  place.  This  is  commonly  known 
as  a  Thiry-Vella  fistula.  In  general  it  has  been  observed 
that  practically  no  fluid  is  secreted  into  the  intestine  with- 
out a  stimulus  of  some  sort.  Electrical  or  mechanical  stim- 
ulation as  well  as  the  introduction  of  food  causes  a  yellowish 
fluid  to  pour  into  the  gut.  PregP''  has  studied  the  secretion 
by  this  method  in  a  lamb.  Here  he  finds  a  continuous  secre- 
tion which  is  increased  after  the  taking  in  of  food.  It  pos- 
sesses a  distinctly  alkaline  reaction,  and  contains  carbonates, 
chlorides,  and  a  considerable  quantity  of  proteid.  It  also 
contains  urea.  For  a  complete  analysis  the  reader  is  re- 
ferred to  Pregl's  article.  The  intestinal  juice  of  the  lamb 
has  no  digestive  action  on  proteids.  There  was  formed  from 
starch  paste  a  fermentable  sugar.  Cane  sugar  and  maltose 
were  inverted,  but  milk  sugar  remained  unchanged. 

The  influence  of  the  nervous  system  on  the  secretion  of 
intestinal  fluid  is  very  clear.  It  was  found  by  Moreau^*  that 
section  of  the  nerves  to  the  intestine  brought  about  a  large 
secretion  of  fluid  into  the  intestine  resembling  closely  that 
obtained  by  a  Thiry-Vella  fistula.  Budge^^  had  previously 
noted  that  extirpation  of  the  ganglia  of  the  coeliac  plexus 
caused  an  increase  of  fluid  in  the  intestine.  The  results  of 
Moreau,  who  carried  out  his  experiments  with  isolated  loops, 
have  been  repeatedly  confirmed,  and  some  question  has 
arisen  as  to  the  nature  of  the  fluid  secreted,  some  authors 


"  Sitzungsb.  d.  k.  Akad.  d.  Wissensch.  Wien,  1864,  Bd,  1. 
"  Untersuchung.   z.   Naturl.   d.   Mensch.   u.   d.   Thiere;    1881;    Bd. 
XIII. 

"  Arch,  f .  d.  gesammte  Physiologie,  Bd.  LXI,  1895,  S.  359. 

"  Centralbl.  d.  Medicin.  Wissensch.,  S.  209,  1868. 

^=  Verhandl.  d.  K.  K.  Leop.  Carol.  Akad.  d.  N.,  Bd.  19,  1860. 


regarding  it  as  a  transudation,  others  as  a  true  secretion. 
It  has  been  compared  by  some  to  the  rice  water  stools  of 
Asiatic  cholera,  and  on  account  of  the  analogy  with  the 
secretion  which  pours  from  the  salivary  gland  after  section 
of  the  chorda  tympani  it  has  been  called  a  paralytic  secre- 
tion. Landois^"  ascribes  the  secretion  to  the  cutting  of  vaso- 
motor nerves  which  causes  circulatory  changes  so  marked 
that  a  transudation  of  fluid  occurs.  In  the  leg,  however,  it 
has  been  shown  that  the  normal  transudation  and  lymph 
formation  are  not  increased  by  section  of  the  nerves.  One 
would  also  expect  to  find  oedema  of  the  intestinal  wall  if 
this  were  a  process  of  transudation  due  to  vascular  changes. 
Such  oedema  does  not  occur. 

The  nature  of  the  fluid  obtained  by  section  of  the  nerves 
to  the  intestine  has  been  studied  by  many  investigators. 
Moreau  described  it  as  a  light  yellow  clear  fluid  with  a 
strongly  alkaline  reaction.  Its  specific  gravity  is  1.008.  It 
contains  carbonates,  chlorides,  organic  materials  and  a  little 
urea.  According  to  Hanau,^'^  the  fluid  contains  no  digestive 
ferments,  although  in  the  dog  he  found  that  in  the  first  part 
of  the  secretion  fibrin  was  digested  to  some  extent  and 
starch  convei-ted  into  sugar.  This  he  ascribed  to  the  pres- 
ence of  pancreatic  juice.  MendeP^  has  recently  worked  on 
this  subject  and  finds  also  that  the  pure  paralytic  secretion 
has  no  digestive  action  on  fibrin,  but  that  there  is  a  slight 
amylolytic  action.  Cane  sugar  and  maltose  are  inverted, 
while  milk  sugar  is  not. 

The  fact  that  the  paralytic  secretion  resembles  very 
closely  the  normal  secretion  both  physically  and  chemically 
seems  to  indicate  that  it  is  a  true  secretion  and  not  a  trans- 
udation. 

Bottazzi^®  has  recently  found  that  an  extract  of  the  small 
intestine  injected  into  the  blood  causes  not  only  an  increase 


^"Lehrbuch  der  Physiologie,  10th  Ed.,  p.  360. 
"  Zeitsch.  f .  Biologie,  Bd.  22,  1886,  p.  195. 
"Arch.  f.  d.  ges.  Physiol.,  Bd.  63,  1896,  p.  425. 
"  Arch,  di  Pisiologia,  1904,  I,  413. 


in  the  fluid  secreted  into  the  intestine,  but  also  an  increase 
in  the  peristaltic  movements.  This  extract  is  an  aqueous 
one,  the  nucleoproteids  being  precipitated  by  acetic  acid. 
It  thus  contains  the  secretin  of  Bayliss  and  Starling  and  is 
capable  of  increasing  also  the  pancreatic  secretion.  -  The 
fluid  produced  in  the  intestine  was  later  analyzed  by  Bot- 
tazzi  and  Gabrieli-"  and  proved  to  be  quite  similar  to  the 
normal  intestinal  secretion.  It  is  of  some  interest  to  note 
that  the  intestinal  secretion  and  the  pancreatic  secretion  are 
simultaneously  augmented  by  the  intravenous  injection  of 
this  extract. 


-"Arcli.  Internationales  de  Physiologie,  1905,  Vol.  Ill,  II,  p.  156. 


CHAPTER  II. 

The  Subcutaneous  and  Intravenous  Injection  of 
Saline  Purgatives. 

Although  it  has  long  been  known  that  many  of  the  vege- 
table purgatives  act  as  well  when  introduced  into  the  circu- 
lation as  when  taken  by  mouth,  it  has  generally  been  stated 
that  saline  purgatives  are  inactive  v/hen  injected  either  sub- 
cutaneously  or  intravenously.  It  has  even  been  claimed  that 
they  have  the  opposite  effect,  causing  constipation.  Claude 
Bernard,^^  however,  states  that  sodi^vm  sulphate  causes 
purgation  when  introduced  into  thj  circulation,  although 
he  gives  no  experiments  to  support  the  assertion.  Buch- 
heim^^  believed  that  intravenous  injection  of  purgative  salts 
produced  no  purgation.  Rabuteau^^  stated  that  the  injec- 
tion of  a  large  amount  of  sodium  sulphate  into  the  blood 
caused  constipation  in  a  dog,  an  experiment  which  he  took 
to  prove  that  the  strong  solution  outside  the  intestine  with- 
drew fluid  from  the  lumen  by  its  endosmotic  power.  Head- 
land-* advanced  the  view  that  all  medicines  act  after  being 
absorbed  into  the  blood,  and  that  saline  cathartics  are  first 
taken  np  into  the  circulation  and  stimulate  the  intestine  in 
being  later  excreted  by  the  intestinal  glands.  Carpente.r 
reported  an  experiment  in  which  he  obtained  a  purgative 
action  by  introducing  magnesium  sulphate  into  the  stomach 

-^  Legons  sur  les  effets  des  substances  toxiques  et  medicamenteuses, 
Paris,  1857. 

^-  Arch,  f .  physiol.  Heilkunde,  1854. 
''  Gaz.  Med.  de  Paris,  1879. 
^  Action  of  Medicines,  1867. 


10 


after  this  organ  had  been  separated  from  the  intestine  by 
a  ligature.  It  was  further  found  by  Vulpian^^  that  small 
doses  of  magnesium  sulphate,  but  not  of  sodium  sulphate, 
acted  as  purgatives  when  injected  subcutaneously.  Hay^® 
gives  an  excellent  resume  of  the  literature  on  this  subject. 
Although  he  considers  it  already  proven  that  purgatives  do 
not  act  when  injected  subcutaneously  or  intravenously,  he 
has  made  a  number  of  experiments  to  confirm  this  idea. 
He  was  unable  to  obtain  any  purgative  effect  in  dogs  and 
cats  by  the  introduction  into  the  blood  of  10%  NagSO^  or 
20%  MgS04.  With  the  subcutaneous  injection  of  these 
salts,  however,  a  purgative  action  was  sometimes  produced. 
This  he  attributed  to  the  local  irritation  of  the  injection.  It 
will  be  noted  that  the  conditions  of  these  experiments  are 
by  no  means  ideal.  Hay  injected  directly  into  the  blood  a 
solution  of  NaoSO^,  which  is  approximately  twice  as  strong 
as  a  solution  of  this  salt  isosmotic  with  the  blood  would  be. 
Similarly  a  solution  of  MgSO^  isosmotic  with  the  blood 
would  be  about  4%  (m/6  Sol"  MgSO^  +  7  HoO  =  4.1  g. 
in  100  c.c).  Hence  the  solution  which  Hay  introduced 
directly  into  the  circulation  was  five  times  as  concentrated 
as  an  isosmotic  solution.  Although  it  is  not  clear  just  what 
abnormal  conditions  would  be  brought  about  by  the  injec- 
tion of  such  concentrated  solutions,  it  is  certain  that  the 
normal  action  of  the  salt  could  not  be  expected  under  these 
circumstances.  This  is  further  shown  by  the  fact  that  Hay 
did  obtain  a  purgative  action  in  some  eases  when  he  injected 
the  salt  solutions  subcutaneously.  Here  the  injury  caused 
by  the  concentrated  solution  was  only  local,  and  the  salt 
itself  was  absorbed  in  small  quantities  and  in  more  dilute 
solution  into  the  blood. 

In  a  large  number  of  experiments  which  have  yielded 
quite  constant  results  I  have  been  unable  to  confirm  the 


'=  Gazette  Medieale,  1873. 

=«  Journal  of  Anatomy  and  Physiology,  Vol.  XVI,  1882,  and  XVII, 
1883. 


11 


idea  generally  held  and  supported  by  Hay  that  subcuta- 
neous and  intravenous  injections  of  saline  purgatives  do  not 
exert  a  purgative  action,  I  have  quite  constantly  found 
that  with  proper  conditions  these  salts  do  produce  increased 
peristalsis  and  also  an  increased  secretion  of  fluid  into  the 
intestine  when  introduced  directly  into  the  circulation  or 
under  the  skin.  In  most  cases  also  an  actual  passage  of 
faeces  was  observed. 

Several  methods  were  used  in  testing  the  action  of  the 
salts  and  it  was  found  that  the  results  could  best  be  studied 
by  observing  the  loops  of  intestine  directly.  In  rabbits 
under  the  influence  of  morphine  (5  c.c.  1%  solution  mor- 
phine hydrochlorate  subcutaneously)  the  abdominal  cavity 
was  laid  open  and  the  loops  of  intestine  carefully  protected 
from  loss  of  heat  and  moisture  while  under  observation.  In 
other  cases  they  were  observed  under  the  surface  of  normal 
sodium  chloride  solution,  a  method  devised  by  van  Braam- 
Houckgeest  and  used  by  him  in  a  long  series  of  experiments. 
In  the  NaCl  solution  the  intestines  normally  remain  almost 
quiet  and  the  effect  on  them  of  stimulating  agents  can  be 
readily  determined.  In  addition  to  this  method  many  ex- 
periments were  made  in  which  animals  were  kept  in  sepa- 
rate cages,  some  acting  as  control  animals,  others  for  ex- 
periment. The  amount  and  character  of  the  faeces  were 
observed  during  several  hours  after  the  administration  of 
the  purgative  and  compared  with  the  control  animals.  The 
solutions  used  were  made  up  as  fractions  of  molecular  solu- 
tions. Thus  to  obtain  a  solution  of  sodium  citrate,  for  ex- 
ample, approximately  isosmotic  with  the  rabbit 's  blood,  one- 
sixth  molecular  weight  of  the  salt  in  grams  (including  water 
of  crystallization)  was  dissolved  in  1,000  c.c.  distilled  water. 
This  gave  an  m/6  solution,  which  was  taken  to  be  approxi- 
mately isotonic  with  the  blood.  The  injections  were  made 
usually  with  a  hypodermic  needle  into  the  marginal  vein  of 
the  rabbit's  ear,  or  into  the  jugular  vein.  Subcutaneous 
injections  were  made  under  the  loose  skin  of  the  back.    In 


12 


most  of  these  experiments  small  rabbits  weighing  from  1,200 
to  1,500  grams  were  used. 

In  studying  the  purgative  action  of  these  salts,  two 
criteria  may  be  considered,  namely,  the  actual  passage  of 
faeces,  and  secondly  merely  the  increase  of  peristalsis-  and 
secretion  not  necessarily  accompanied  by  defaecation.  The 
former  is  of  course  the  object  of  purgation,  and  unless  a 
salt  produces  an  actual  passage  of  faeces  it  cannot  strictly 
be  termed  a  purgative.  When  this  has  been  established, 
however,  it  is  of  much  greater  advantage  to  use  the  other 
criterion  in  studying  the  action  of  the  solutions  on  the 
intestine.  Any  salt  which  in  small  doses  produces  an  in- 
creased peristalsis  will  with  a  more  prolonged  action  and 
perhaps  larger  doses  produce  actual  purgation.  Therefore 
in  the  first  rough  test  as  to  the  action  of  the  salts  I  have 
used  the  actual  passage  of  faeces  as  the  criterion  of  the 
action.  In  this  case  no  morphine  is  given  the  animal  and 
its  intestines  are  not  exposed  as  in  the  other  experiments 
where  the  movements  are  directly  watched.  In  these  tests 
the  animals  were  kept  in  boxes,  the  bottom  of  each  of  which, 
was  covered  by  a  large  sheet  of  paper.  During  a  certain 
time  preceding  the  injection  of  any  solution  the  animals 
were  watched  and  the  faeces  collected  and  weighed.  Half 
of  the  animals  were  kept  as  controls,  and  the  rest  subjected 
to  injections  of  various  solutions.  The  average  weight  of 
the  normal  faeces  was  compared  with  the  weight  of  the 
faeces  passed  during  the  same  time  by  the  animals  receiv- 
ing the  injections.  The  faeces  were  collected  and  weighed 
each  hour  during  the  first  six  hours  following  the  first  injec- 
tion. The  chief  purgative  effect  usually  took  place  during 
the  first  two  hours.  Althou,gh  there  was  considerable  indi- 
vidual variation  in  the  rabbits,  there  was  found  to  be  a 
constant  increase  in  the  amount  of  faeces  following  the  sub- 
cutaneous or  intravenous  injection  of  one  of  the  salts.  This 
amount  varied  from  two  to  six  times  the  average  normal 
weight.     Sometimes  the  increase  was  much  greater  and  in 


13 


many  cases  the  nature  of  the  faeces  was  much  changed. 
The  normal  faeces  of  the  rabbit  consist  of  dry  hard  defi- 
nitely formed  masses.  Following  the  purgative,  they  be- 
come soft  and  unformed,  and  may  as  in  the  case  of  NaF  and 
BaClg  be  semifluid. 

The  amount  of  sodium  citrate,  sulphate,  or  tartrate 
necessary  to  produce  purgation  is  about  the  same  in  each 
case :  10  c.c.  m/6  solution  injected  subcutaneously,  followed 
10  minutes  later  by  a  second  injection  of  5  c.c.  of  this  solu- 
tion and  10  minutes  after  this  by  a  third  similar  injection, 
usually  produces  well  marked  passages  of  faeces.  Some- 
times the  result  is  obtained  with  a  single  injection,  but  a 
prolonged  action  of  the  salt  seems  to  be  more  favorable. 
With  sodium  fluoride  and  barium  chloride  much  smaller 
doses  are  necessary.  Sodium  fluoride  is  more  poisonous 
than  the  citrate  or  sulphate,  but  if  injected  slowly  as  much 
as  10  c.c.  m/6  solution  can  be  safely  introduced  under  the 
skin.  This  produces  in  a  little  over  an  hour  well  marked 
purgation,  usually  with  the  passage  of  soft  or  semifluid 
faeces.  Barium  chloride  is  a  well  known  saline  purgative 
among  veterinary  surgeons,  who  always  administer  it  in- 
travenously or  subcutaneously.  In  order  to  purge  a  horse 
weighing  1,000  pounds,  0.75  g.  BaCL  is  usually  given  sub- 
cutaneously. Its  action  is  very  constant.  When  given  to 
rabbits  I  have  found  that  2  c.c.  m/6  solution  BaCL  injected 
under  the  skin  always  produces  a  well  marked  purgative 
action  with  the  passage  of  large  quantities  of  semifluid 
faeces.  When  injected  intravenously  it  is  better  to  mix  the 
BaCL  with  about  five  times  its  volume  of  m/6  NaCl.  The 
injection  of  1  c.c.  of  a  mixture  of  1  c.c.  m/6  BaCL  +  5  c.c. 
m/6  NaCl  produces  purgation  and  a  passage  of  semifluid 
faeces.    This  action  is  much  more  rapid  than  with  NaF. 

These  experiments  demonstrate  the  fact  that  the  intra- 
venous or  subcutaneous  injection  of  saline  purgatives  do 
produce  purgation  and  an  actual  passage  of  faeces.  In 
order,  however,  to  study  the  action  of  the  salts  more  min- 


14 


utely  another  method  was  resorted  to,  namely,  that  of  open- 
ing the  abdomen  and  directly  observing  the  loops  of  intes- 
tine. In  a  large  number  of  experiments  it  is  not  difficult  to 
become  quite  familiar  with  the  movements  normally  present, 
and  with  the  disturbances  produced  by  such  external  influ- 
ences as  cooling,  drying,  etc.  These  influences  can  by  proper 
precautions  be  practically  eliminated. 

By  this  method  it  was  possible  to  study  the  influence  of 
the  salts  on  the  two  great  activities  of  the  intestine,  namely, 
the  muscular  movements  and  the  glandular  activity.  Their 
action  on  the  secretion  is  treated  of  in  a  later  chapter  and 
can  only  be  mentioned  here.  The  increase  of  these  two 
activities  by  means  of  a  salt  is  the  essential  action  of  a 
purgative,  and  leads,  if  sufficiently  prolonged,  to  purgation 
and  to  the  passage  of  faeces.  This  passage  of  faeces  does 
not  take  place  so  readily  when  the  intestines  are  exposed 
and  the  animal  is  under  the  influence  of  morphine  as  it  does 
in  a  normal  animal.  The  exposure  of  the  intestine  for  an 
hour  or  more  apparently  renders  this  action  difficult,  al- 
though not  uncommonly  the  actual  passage  of  faeces  is  ob- 
served under  these  circumstances.  This  is  always  the  case 
with  BaCL. 

In  a  rabbit  with  its  intestines  visible  it  was  found  that 
the  injection  of  1-2  c.c.  m/8  or  m/6  sodium  citrate  solution 
into  the  jugular  vein  of  a  rabbit  brings  about  a  very  marked 
increase  in  the  peristaltic  movements,  which  begins  from  1 
to  2  minutes  after  the  injection.  The  loops  are  set  in  active 
movements  and  become  firm  and  rounded  so  that  they  seem 
to  occupy  a  greater  volume.  The  movements  consist  not 
only  of  swinging  pendulum  movements,  but  of  real  peris- 
taltic waves  which  cause  the  contents  of  the  intestine  to 
move  along  the  gut  so  that  they  may  be  watched  through  the 
thin  walls.  The  morphine  narcosis  of  the  animal  does  not 
seem  to  interfere  with  this  action  of  the  salt. 

When  these  salt  solutions  are  administered  subcuta- 
neously  they  do  not  act  at  once,  as  in  the  case  of  intra- 


15 


venous  injections.  An  interval  of  10  to  15  minutes  elapses 
after  the  subcutaneous  injection  before  any  influence  on 
the  intestine  is  noticed.  The  movements  then  begin  as  be- 
fore, the  peristaltic  movements  and  pendulum  movements 
gradually  increasing  in  force.  In  addition  to  the  greater 
time  required  for  the  action  of  the  salt  when  administered 
in  this  way,  it  is  also  necessary  to  give  a  larger  amount 
than  in  intravenous  injections;  5-10  c.c.  m/8  or  m/6  solu- 
tion of  sodium  citrate  must  be  introduced  subcutaneously 
in  order  to  produce  increased  peristalsis. 

If  the  solution  be  introduced  into  the  stomach  or  intes- 
tine a  similar  increase  in  peristalsis  is  brought  about,  but 
only  after  a  considerable  interval.  Usually  no  effect  is  ob- 
tained until  10  to  15  minutes  after  the  injection  of  the  salt 
into  the  lumen  of  the  gut.  The  injection  may  be  made  by 
piercing  the  wall  of  the  intestine  or  stomach  with  a  hypo- 
dermic needle,  and  forcing  the  fluid  into  the  lumen.  The 
quantity  of  the.  solution  necessary  to  produce  increased 
peristalsis  is  about  the  same  as  when  introduced  subcuta- 
neously. The  movements  begin  not  particularly  in  the  part 
of  the  intestine  containing  the  solution,  but  simultaneously 
in  all  parts. 

To  any  one  making  these  experiments  there  can  be  no 
doubt  that  the  increased  peristalsis  is  the  direct  result  of 
the  injection  of  the  salt.  It  can  be  readily  proven  in  the 
following  way:  As  will  be  shown  in  a  later  chapter,  the 
peristalsis  and  secretion  caused  by  the  saline  purgatives  can 
be  inhibited  by  the  administration  of  calcium  or  magnesium 
chloride.  If  now  in  a  rabbit  in  which  the  intestine  has 
been  set  into  active  motion  by  the  intravenous  injection  of 
sodium  citrate,  a  small  quantity  of  m/6  CaCL  be  admin- 
istered intravenously,  all  of  these  movements  cease  within 
a  minute  or  two.  A  second  injection  of  a  slightly  greater 
quantity  of  m/6  sodium  citrate  will  overcome  this  action 
and  cause  active  peristalsis  to  begin  again.  These  actions 
cannot  be  due  to  anything  but  the  solutions  introduced. 


16 


It  is  evident  also  in  watching  the  action  oi  these  salts 
that  they  produce  increased  peristalsis  much  more  rapidly 
and  powerfully  when  introduced  intravenously  than  when 
placed  in  the  lumen  of  the  stomach  or  intestine.  A  much 
smaller  dose  also  is  required  to  produce  this  effect.  They 
therefore  cannot  act  because  of  their  presence  in  the  lumen 
of  the  gut,  or  because  of  their  being  subsequently  secreted 
into  the  lumen.  When  introduced  into  the  stomach  or  in- 
testine they  must  first  be  absorbed  into  the  blood  before 
they  can  reach  the  muscular  and  glandular  tissues  upon 
which  they  act.  They  therefore  act  more  slowly  and  only 
in  larger  quantities  when  administered  in  this  way. 

Experiments  similar  to  the  above  were  made  with  a 
number  of  salts,  including  sodium  sulphate,  fluoride,  tar- 
trate, phosphate  and  oxalate,  barium  chloride,  and  magne- 
sium sulphate.  It  was  found  that  intravenous  and  subcu- 
taneous injections  of  all  of  these  were  active  in  producing 
a  greater  or  less  increase  in  peristalsis.  Sodium  sulphate 
acted  in  this  respect  very  much  as  sodium  citrate  did.  The 
latter,  however,  tended  to  produce  muscular  twitchings  in 
the  voluntary  muscles,  a  phenomenon  which  will  be  spoken 
of  later.  Sodium  sulphate  on  the  other  hand  could  be  in- 
troduced into  the  blood  in  relatively  large  quantities  with- 
out producing  any  evil  effects.  The  action  of  sodium  sul- 
phate on  the  intestine  was  found  to  be  somewhat  less  than 
that  of  sodium  citrate ;  but  almost  constantly  2-3  c.c.  m/6 
Na^SO^  injected  into  the  marginal  vein  of  the  ear  caused  a 
marked  increase  in  the  peristaltic  movements  of  the  intes- 
tine. I  cannot  at  all  agree  with  Hay  and  earlier  writers 
who  affirm  that  sodium  sulphate  injected  intravenously  pro- 
duces no  purgative  effect.  In  all  my  experiments  I  have 
found  it  to  have  a  very  definite  effect  when  introduced  in 
this  manner,  and  I  can  only  attribute  their  results  to  the 
concentrated  solutions  used,  or  to  other  unfavorable  con- 
ditions. 

The  injection  of  solutions  of  sodium  fluoride  produces 


17 


very  active  movements,  althougli  only  small  quantities  can 
be  administered  on  account  of  its  poisonous  nature. 

Barium  chloride  is  even  more  poisonous  and  only  the 
most  minute  doses  can  be  given.  It  is,  however,  by  far  the 
most  powerful  of  all  these  purgative  salts.  Its  action  is 
extremely  rapid  and  violent.  When  given  intravenously  it 
is  best  to  mix  it  with  about  five  times  its  volume  of  m/6 
NaCl  solution.  Thus  1  c.c.  of  a  mixture  of  5  c.c.  m/6  NaCl 
+  1  c.c.  m/6  BaClg  injected  into  the  circulation  causes  al- 
most immediately  most  violent  intestinal  movements.  The 
loops  contract  so  that  they  resemble  white  firm  cords.  They 
rise  up  from  one  another  so  that  they  seem  to  stand  erect 
and  the  squirming,  twisting  movements  become  extremely 
active.  The  intestinal  contents  are  hastened  on  and  can  be 
watched  through  the  thin  walls  moving  rapidly  from  loop 
to  loop.  The  actual  passage  of  faeces  takes  place  in  a  very 
short  time.  It  begins  with  solid  faecal  masses,  followed 
quickly  by  semifluid  faeces.  The  quantity  passed  is  some- 
times very  considerable.  As  will  be  shown  in  a  later  chap- 
ter, the  injection  of  BaClg  into  the  blood  causes  not  only  an 
extensive  increase  in  the  peristaltic  movements,  but  brings 
about  also  an  increase  in  the  quantity  of  fluid  secreted  into 
the  intestine. 

The  subcutaneous  injection  of  2-3  c.c.  m/6  BaClg  pro- 
duces in  5-10  minutes  an  effect  quite  similar  to  that  de- 
scribed for  the  intravenous  injection  of  the  salt.  A  rabbit 
weighing  1,200-1,500  g.  does  not,  however,  usually  recover 
from  a  dose  greater  than  2.5-3  c.c.  m/6  BaCla  given  subcu- 
taneously,  and  a  smaller  quantity  is  sufficient  to  produce 
purgation.  Boehm^^  gives  as  the  lethal  dose  of  BaCla  when 
given  intravenously  for  rabbits  0.1-0.2  g.,  for  eats  0.0?- 
0.05  g.,  for  dogs  0.1-0.2  g.  When  given  subcutaneously  it 
is  0.12-0.18  g.  for  rabbits  and  cats  and  0.3  g.  for  dogs. 

When  BaCla  is  taken  into  the  stomach  it  is  absorbed 
quite  slowly,  but  its  effects  are  similar  to  those  described 
"  Arch,  f .  exp.  Path.  u.  Pharm.,  Bd.  3,  1875,  p.  215. 


18 

above.  Active  peristaltic  movements  and  purgation  result, 
and  in  many  cases  vomiting  is  seen  in  dogs. 

It  is  clear  from  these  experiments  that  all  salts  do  not 
act  equally  on  the  intestine.  Sodium  chloride  may  be  in- 
troduced in  large  quantities  into  the  circulation  without 
causing  increased  peristalsis  or  defaecation.  Sodium  oxa- 
late and  phosphate  (Na2HP04)  exert  only  a  slight  action. 
Sodium  phosphate,  according  to  Bunge,  increases  the  fluid 
in  the  intestine.  Sodium  tartrate  produces  quite  active 
movements  of  the  intestine  and  is  considerably  stronger  in 
its  action  than  either  the  oxalate  or  phosphate.  Sodium 
citrate  and  sulphate  as  described  above  are  quite  constant 
and  vigorous  in  their  action,  while  barium  chloride  is  by 
far  the  most  powerful  of  all  these  saline  purgatives.  So- 
dium fluoride  also  acts  very  rapidly. 

In  addition  to  their  action  on  the  intestine,  some  of 
these  salts  affect  the  salivary  gland.  After  the  injection  of 
BaCla  there  is  often  so  great  a  flow  of  saliva  that  it  falls  in 
drops  from  the  mouth.  This  phenomenon  is  not  constant, 
however,  and  seems  to  follow  only  large  doses.  Sodium 
fluoride  has  sometimes  the  same  effect.  I  have  not  noticed 
any  influence  exerted  by  the  other  purgative  salts  upon  the 
salivary  secretion.  It  is  further  of  not  infrequent  occur- 
rence to  have  a  repeated  evacuation  of  urine  after  the  ad- 
ministration of  BaCla-  Although  this  cannot  be  attrib- 
uted to  a  direct  increase  of  the  secretion  of  urine,  it  is  in- 
teresting to  note  in  this  connection  some  later  experiments 
in  which  it  was  shown^^  that  when  the  flow  of  urine  in  a 
rabbit  had  been  well  established  by  the  injection  of  m/6 
NaCl  solution  into  the  circulation,  the  addition  of  a  minute 
quantity  of  BaClg  to  the  NaCl  solution  caused  a  very  con- 
siderable increase  in  the  secretion  of  urine  from  the  kidney. 
A  quantity  of  not  more  than  1/8  c.c.  m/8  BaClg  must  be 

=^  MacCallum,  J.  B. :  Journal  of  Exp.  Zoology,  Vol.  I,  No.  1, 1904. 
Preliminary  Eeport,  University  of  California  Publications,  Physiology, 
Vol.  I,  No.  10,  p.  81,  1904. 


19 


given  intravenously  to  produce  this  effect.  If  1  c.c.  m/8 
BaCl,  be  injected  intravenously  at  one  time  the  flow  of 
urine  suddenly  stops.  This  seems  to  be  due  either  to  a  sud- 
den constriction  of  the  musculature  of  the  urinary  pas- 
sages and  pelvis  of  the  kidney  by  which  the  lumen  is  cut  off, 
or  to  a  similar  constriction  of  the  blood  vessels  of  the  kid- 
ney. In  either  case  the  action  of  BaCla  in  stopping  the 
secretion  is  mechanical  and  has  to  do  with  its  power  of 
causing  violent  muscular  contractions  rather  than  with  its 
capacity  for  increasing  the  secretory  activity.  Although 
there  is  apparently  one  action  for  BaClg  on  the  flow  of 
urine  when  given  in  small  doses  and  quite  the  opposite 
action  when  it  is  given  in  larger  quantities,  the  two  actions 
are  in  reality  quite  distinct,  one  being  exerted  on  the  secre- 
tory cells  of  the  kidney  and  the  other  on  the  musculature 
of  either  the  urinary  passages  or  of  the  blood  vessels  of  the 
kidney. 

In  addition  to  their  action  on  the  intestine  and  in  some 
cases  the  kidney  and  salivary  gland,  these  salts  produce 
an  interesting  condition  of  the  voluntary  muscles.  As  men- 
tioned above,  Loeb  was  able  to  produce  muscular  twitchings 
in  the  muscle  of  a  frog  by  immersing  the  muscle  in  solu- 
tions of  these  various  salts.  He  also  produced  muscular 
twitching  in  a  living  frog  by  injecting  sodium  citrate  into 
the  dorsal  lymph  sacs.  I  have  found  that  a  subcutaneous 
injection  of  10  c.c.  m/1  sodium  citrate  produces  in  a  rabbit 
well  marked  twitchings  of  the  muscles  all  over  the  body. 
These  are  very  noticeable  in  the  gluteal  region.  They  begin 
almost  immediately  in  the  neighborhood  of  the  injection, 
but  only  after  an  interval  of  20  to  25  minutes  on  the  op- 
posite side  of  the  body.  If  the  animal  be  placed  on  the 
floor  it  moves  with  a  peculiar  incoordinated  gait.  The  hind 
legs  are  dragged  and  very  little  headway  is  made.  If  the 
rabbit  be  held  up  by  the  ears,  the  feet  tremble,  and  if 
touched  the  legs  jerk  away  violently  and  usually  become 
rigid.    There  are  sometimes  tetanus-like  contractions  of  the 


20 


limbs,  and  occasionally  general  convulsions  of  greater  or 
less  severity.  In  one  rabbit  I  gave  daily  injections  of  5  c.c. 
m/1  sodium  citrate  subcutaneously  throughout  one  month. 
For  some  time  after  the  injections  had  been  discontinued 
the  hypersensitiveness  seemed  to  persist.  It  seemed  pos- 
sible from  this  that  a  chronic  state  of  increased  irritability 
might  be  produced.  No  conclusion,  however,  can  be  drawn 
from  this  one  experiment  since  the  irritation  caused  by  the 
repeated  injections  might  have  had  some  influence.  It  is  a 
subject  which  is  of  interest  for  further  experiment,  on  ac- 
count of  the  similarity  such  a  chronic  condition  bears  to 
the  various  chronic  hypersensitive  conditions  found  in  hu- 
man beings. 

In  looking  over  the  experiments  made  by  various  inves- 
tigators on  this  subject  it  will  be  noticed  that  their  results 
are  inconstant  and  contradictory.  This  can  only  be  the  re- 
sult of  imperfect  technique  and  unfavorable  conditions,  or 
of  the  adoption  of  a  criterion  of  the  action  of  the  salt,  which 
is  uncertain.  As  mentioned  above,  the  solutions  used  in 
many  cases  were  not  at  all  those  most  favorable  for  intro- 
duction into  the  blood.  The  very  concentrated  solutions 
used  by  Hay  rendered  the  conditions  obviously  unfavor- 
able. If  in  addition  to  watching  for  the  actual  passage 
of  faeces  these  experimenters  had  observed  the  intestines 
directly  the  results  would  of  necessity  have  been  more  uni- 
form. 

My  own  experiments  have  given  quite  uniform  results, 
so  much  so  that  the  production  of  increased  peristalsis  in 
rabbits  by  the  intravenous  injection  of  one  of  the  saline 
purgatives  has  come  to  be  a  class  experiment  with  the  stu- 
dents in  the  medical  school  here.  The  increased  secretion 
into  the  intestine  produced  by  the  same  means  requires 
greater  care  in  protecting  the  loops  from  loss  of  heat  and 
moisture.  For  any  one  to  convince  himself  that  a  salt  may 
act  as  a  purgative  when  injected  subcutaneously  or  intra- 
venously it  is  only  necessary  to  introduce  a  small  amount 


21 


of  BaCla  into  the  blood  or  under  the  skin  of  a  rabbit.  The 
evacuation  of  large  quantities  of  semifluid  faeces  and  the 
violent  intestinal  movements  leave  no  room  for  doubt  as  to 
the  action  of  the  salt.  The  fact  that  the  intravenous  and 
subcutaneous  administration  of  this  salt  as  a  purgative  by 
veterinarians  is  in  general  use  should  be  sufficient  proof. 

The  milder  salts  such  as  sodium  citrate  and  sulphate 
must,  as  stated  above,  be  given  in  larger  quantities,  and  a 
more  prolonged  action  is  necessary. 

As  will  be  described  in  detail  in  the  next  chapter,  the 
application  of  solutions  of  these  salts,  isosmotic  with  the 
blood,  to  the  peritoneal  surfaces  of  the  intestine  cause  not 
only  increased  peristalsis  and  increased  secretion  of  fluid 
into  the  intestine  but  also  bring  about  an  evacuation  of 
faeces.  This  fact  alone  proves  that  it  is  not  necessary  to 
introduce  the  purgative  salt  into  the  stomach  or  intestine. 
The  action  on  the  intestine  in  this  case  takes  place  more 
rapidly  than  in  any  other  method  of  administration.  The 
solution  seems  to  be  directly  absorbed  through  the  perito- 
neal covering  and  to  come  into  contact  with  the  muscles 
and  glands,  and  perhaps  the  nerves  of  the  intestine.  These 
tissues  are  immediately  set  into  activity. 

In  the  intravenous  or  subcutaneous  injections  of  the 
salts  it  is  necessary  to  mention  a  peculiarity  of  magnesium 
sulphate.  This  salt  of  course  acts  as  a  purgative  because 
it  is  a  sulphate  and  not  on  account  of  the  presence  of  mag- 
nesium. As  shown  later  on,  magnesium  chloride  has  an  ef- 
fect quite  opposite  to  this.  In  injecting  MgSO^  into  the 
blood  the  greatest  care  must  be  taken  because  of  its  pecu- 
liarly poisonous  nature  when  rapidly  absorbed.  Rabbits 
frequently  die  suddenly  from  an  injection  of  a  relatively 
small  quantity.  This  fact  has  been  mentioned  by  a  number 
of  authors,  and  is  repeated  here  only  as  a  warning  against 
its  too  rapid  injection,  possibly  in  human  beings. 

It  may  be  mentioned  here  also  that  Bottazzi^®  has  found 

=»  Arch,  di  Fisiologia,  1904,  I,  413. 


22 


that  the  intravenous  injection  of  an  extract  of  the  small 
intestine  containing  secretin  causes  not  only  a  well  marked 
increase  in  the  secretion  of  fluid  into  the  intestine,  but  also 
produces  increased  peristaltic  activity.  It  at  the  same  time 
increases  the  pancreatic  secretion.  .     , 


CHAPTER  III. 

The  Local  Application  of  Saline  Solutions  to  the 
Peritoneal  Surfaces  of  the  Intestine. 

In  the  last  chapter  it  has  been  shown  that  the  subcuta- 
neous and  intravenous  injections  of  solutions  of  various 
saline  purgatives  produce  a  characteristic  purgative  effect; 
and  that  similar  injections  of  calcium  or  magnesium  chlo- 
ride inhibit  this  action  and  bring  the  intestines  to  rest. 

I  have  found  also  that  solutions  of  these  salts  have  the 
same  effect  when  applied  directly  to  the  peritoneal  surface 
of  the  intestine.  Thus  if  a  solution  of  sodium  citrate  or 
sulphate,^"  for  example,  be  poured  over  the  intestine  those 
loops  which  are  moistened  by  the  solution  will  become  active 
within  one  minute.  After  a  very  short  time  the  remaining 
loops  are  also  set  in  motion.  These  movements  may  be  en- 
tirely inhibited  by  pouring  on  the  loops  a  solution  of  cal- 
cium or  magnesium  chloride.  The  following  description  of 
these  experiments  is  taken  directly  from  my  paper  which 
appeared  two  years  ago.^^ 

The  intestines  of  a  rabbit  under  the  influence  of  mor- 
phine were  exposed.  On  a  small  group  of  coils  there  were 
poured  3  c.c.  m/6  sodium  citrate  solution.  Almost  imme- 
diately  (within  1  minute)   the  loops  became  very  active. 

'"  Pohl  (Arch.  f.  exp.  Path.  u.  Pharm.,  Bd.  34,  S.  87)  stated  that 
all  sodium  and  ammonium  salts  increased  the  peristalsis  when  applied 
to  the  peritoneal  surface  of  the  intestine. 

=1  MacCallum,  J.  B. :  Amer.  Journ.  Physiol.,  Vol.  X,  No.  V,  1904, 
p.  259. 


24 


Strong  contractions  of  the  muscle  coats  took  place.  After 
a  few  minutes  the  other  loops  were  also  set  in  movement, 
so  that  the  whole  small  intestine  showed  active  peristalsis. 
The  citrate  solution  was  then  washed  off  by  m /6  NaCi  so- 
lution, and  about  3  c.c.  m/6  CaClg  solution  poured-  on  the 
loops.  The  peristaltic  movements  were  promptly  sup- 
pressed, and  the  intestine  remained  quiet.  By  the  further 
addition  of  citrate  solution,  the  coils  were  set  in  active 
movement  once  more,  and  by  the  subsequent  application  of 
calcium  chloride  solution  again  inhibited.  This  was  re- 
peated many  times  (sixteen)  and  apparently  might  have 
been  continued  as  long  as  the  intestine  remained  alive. 

The  same  results  were  obtained  by  using  instead  of  the 
sodium  citrate  solution,  a  solution  of  barium  chloride,  so- 
dium sulphate,  fluoride,  bromide,  iodide,  phosphate  (Nag 
PO4),  oxalate  or  tartrate.  Local  application  of  solutions  of 
any  of  these  salts  produces  increased  peristaltic  activity. 
Solutions  of  sodium  chloride  have  a  very  slight  action  of 
the  same  character.  On  the  other  hand,  the  intestinal  move- 
ments are  equally  inhibited  by  calcium  chloride  and  magne- 
sium chloride,  while  strontium  chloride  has  a  similar  but 
less  powerful  inhibiting  action. 

In  testing  those  salts  with  which  it  was  necessary  to  use 
dilutions  greater  than  m/8,  the  dilution  was  made  with  a 
neutral  fluid  consisting  of  sodium  chloride  and  magnesium 
chloride.  It  was  found  that  m/6  NaCl  solution  increased 
to  a  very  slight  extent  the  peristaltic  movements.  By  add- 
ing to  10  c.c.  m/6  NaCl,  0.5  c.c,  m/6  MgClg,  a  fluid  was 
obtained  which  had  apparently  neither  stimulating  nor  in- 
hibiting effects.  In  addition  to  solutions  made  up  by  dilu- 
tion with  this  neutral  fluid,  others  were  used  in  which  the 
salt  solutions  were  diluted  with  distilled  water.  Practically 
the  same  results  were  obtained  in  both  cases.  It  was  found 
that  1  c.c.  m/320  BaCla  solution  applied  locally  to  the  in- 
testine is  sufficient  to  cause  strong  peristaltic  movements  in 
a  rabbit.    This  quantity  contains  about  0.00076  gm.  barium 


25 


chloride.  In  the  case  of  sodium  citrate,  the  concentration 
must  be  considerably  greater.  No  solution  of  this  salt  more 
dilute  than  m/80  is  active  in  a  rabbit.  Of  all  the  purgative 
salts,  barium  chloride  is  by  far  the  most  powerful.  If  a 
drop  of  m/8  BaCls  be  placed  on  the  serous  surface  of  an 
intestinal  loop,  or  if  a  small  area  be  moistened  with  this 
solution  by  means  of  a  camel's  hair  brush,  the  muscle  be- 
neath the  moistened  area  wiU  almost  immediately  contract 
so  that  a  ring-like  constriction  of  the  intestine  is  formed. 
This  often  is  so  sharply  marked  that  it  suggests  the  effect 
produced  by  tying  a  ligature  around  the  intestine.  This 
constriction  remains  for  a  few  moments,  and  then  gradually 
moves  along  the  loop  in  the  direction  of  the  normal  peris- 
talsis. If  the  solution  be  injected  into  the  muscle  of  the 
intestine  at  any  point  with  a  hypodermic  needle,  a  similar 
sharp  constriction  takes  place.  If  also  a  few  drops  be  in- 
jected directly  into  a  branch  of  the  superior  mesenteric 
artery,  all  that  part  of  the  loop  supplied  by  the  arterial 
branch  will  contract  violently.  These  statements  are  true 
also  in  the  case  of  sodium  citrate,  fluoride,  sulphate,  etc. ; 
the  action  of  these  salts,  however,  is  less  powerful. 

It  must  be  added  here  also  that  the  actual  passage  of 
faeces  may  be  produced  within  an  hour  by  the  application 
of  the  purgative  salts  to  the  serous  surfaces  of  the  intestine. 
This  takes  place  most  quickly  with  barium  chloride.  It  is 
possible  to  observe  directly  through  the  semi-transparent 
walls  of  the  intestine  the  rapid  passage  of  faecal  masses 
from  one  loop  to  another. 

The  intestines  of  the  rabbit  are  apparently  much  more 
sensitive  to  the  action  of  sodium  citrate  and  sulphate  than 
are  those  of  the  dog  or  cat.  Barium  chloride,  on  the  con- 
trary, acts  with  equal  strength  in  all  these  animals.  In  a 
rabbit,  the  intestines  are  always  set  in  active  peristaltic 
movement  by  contact  with  m/8  sodium  citrate  solution ;  and 
even  much  more  dilute  solutions  are,  as  a  rule,  effective.  In 
a  cat,  however,  it  was  found  that  an  m/8  solution  of  sodium 


26 


citrate  has  practically  no  effect,  while  a  5/8m  solution  sets 
the  intestine  in  active  motion.  In  a  dog  also,  m/S  sodium 
citrate  solution  is  usually  ineffective.  Similarly  an  m/8  so- 
dium sulphate  solution  is  inactive  in  a  dog  while  an  m/2 
solution  of  the  same  salt  starts  up  distinct  peristalsis. .  In 
the  cat  and  dog  also  the  peristalsis  may  be  inhibited  by 
calcium  or  magnesium  chloride,  as  shown  in  the  following 
experiments.  The  intestines  of  a  cat  were  exposed  in  the 
usual  manner,  and  an  m/8  solution  of  sodium  citrate  was 
applied  to  the  serous  surface  of  the  loops.  There  was  no 
increased  movement.  There  were  then  poured  on  the  loops 
a  few  cubic  centimetres  of  a  mixture  of  5  c.c.  5/8m  sodium 
citrate  and  5  c.c.  5/8m  CaClg.  The  loops  remained  motion- 
less. After  waiting  a  considerable  time  (15  minutes),  a 
5/8m  solution  of  sodium  citrate  alone  was  poured  on  the 
intestine.  Almost  immediately  they  became  very  active; 
and  the  peristalsis  continued  until  calcium  chloride  was 
again  applied.  The  loops  then  came  to  a  standstill.  The 
difference  in  susceptibility  to  the  action  of  citrate  which 
exists  between  rabbits  on  the  one  hand,  and  dogs  and  cats 
on  the  other,  may  be  in  some  way  connected  with  their 
being  herbivorous  and  carnivorous  animals  respectively. 

The  action  of  the  sodium  citrate,  sulphate,  fluoride,  etc., 
when  applied  locally,  may  be  inhibited  by  the  administra- 
tion of  an  approximately  equal  quantity  of  calcium  or  mag- 
nesium chloride  of  the  same  concentration.  The  counter- 
action of  the  effect  of  barium  chloride,  however,  requires  a 
much  greater  concentration  of  calcium.  Using  equal  quan- 
tities of  the  two  salts,  the  action  of  the  barium  is  usually 
not  inhibited,  a  fact  which  I  have  previously  stated.  With 
greater  concentrations  of  the  calcium  chloride,  the  antag- 
onistic action,  however,  is  clear.  This  is  shown  in  the  fol- 
lowing experiment:  Applied  locally  to  the  intestine  of  a 
rabbit  1  c.c.  m/320  BaCla  solution  caused  active  peristaltic 
movements.  The  application  of  1  c.c.  m/320  CaClg  solution 
exercised  no  inhibiting  effect  whatever.     The  same  quan- 


27 


tity  of  ni/40  CaCL  was  then  poured  on  the  loops,  and  a 
slight  but  distinct  quieting  of  the  loops  took  place.  The 
addition  of  1  c.c.  m/6  CaCl,  caused  the  loops  to  become 
entirely  motionless.  After  waiting  a  considerable  time,  1 
c.c.  m/8  BaCL  was  poured  on  the  intestine.  Immediately 
violent  peristaltic  movements  took  place.  Several  c.c.  m/6 
CaCla  exercised  practically  no  inhibiting  influence;  while 
2  c.c.  5/8m  CaClg  solution  suppressed  the  movements  en- 
tirely for  a  short  time. 

The  question  concerning  the  exact  seat  of  action  of  the 
purgative  salts  remains  still  unanswered.  Whether,  upon 
being  absorbed  into  the  blood,  they  act  on  the  central  nerv- 
ous system  is  not  known.  There  is  no  evidence  to  show  that 
this  is  the  case.  It  seems  certain,  on  the  other  hand,  from 
the  experiments  here  described,  that  they  undoubtedly 
have  a  peripheral  action  either  on  the  peripheral  nervous 
mechanism  or  on  the  muscle  cells  themselves.  It  is  impos- 
sible to  prove  that  there  is  no  action  on  the  central  nervous 
system,  and  at  present  it  seems  impossible  to  prove  whether 
the  peripheral  action  is  directly  on  the  nerves  or  on  the 
muscles.  The  existence  in  the  walls  of  the  intestine  of  the 
ganglionic  plexuses  of  Auerbach  and  Meissner  must  be 
taken  into  consideration;  and  with  the  methods  available 
there  seems  to  be  no  way  of  distinguishing  the  action  on 
these  plexuses  and  the  direct  action  on  the  muscle  cells. 
The  ultimate  effect  is  on  the  muscles  and  glands;  and  the 
fact  that  an  entirely  local  ring-shaped  constriction  can  be 
brought  about  by  the  local  application  of  a  drop  of  one  of 
the  salt  solutions  to  the  surface  of  the  intestine  would  seem 
to  indicate  that  only  a  small  group  of  the  circular  muscle 
fibres  themselves  is  affected.  The  fact  that  the  nerve  plex- 
uses form  a  continuous  network,  and  are  intimately  related 
in  their  various  parts,  would  suggest  that  the  occurrence  of 
an  action  on  these  plexuses  confined  to  so  small  an  area  is 
improbable.  The  discussion  of  the  exact  location  of  the 
action  is,  however,  of  relatively  little  importance,  as  com- 


28 


pared  with  the  main  facts  shown  by  these  experiments, 
namely,  that  it  is  possihle  to  produce,  by  the  local  applicd'- 
tion  of  a  purgative  salt  to  the  serous  surface  of  the  intes- 
tine, a  striking  increase  in  peristalsis,  and  to  suppress  these 
movements  hy  a  similar  application  of  solutions  of  calcium, 
magnesium,  or  strontium  chloride. 

These  experiments  also  seem  to  decide  the  question  as 
to  whether  the  salt  solutions  act  after  being  absorbed  into 
the  blood  or  only  when  placed  in  the  intestine.  According 
to  Hay^^  and  others,  the  salt  which  is  absorbed  into  the  cir- 
culation has  no  effect  and  the  only  action  is  produced  by 
that  which  remains  in  the  intestine.  This  is  obviously  not 
true  since  the  solutions  act  much  more  rapidly  and  more 
powerfully  when  applied  to  the  outside  of  the  intestine,  i.e., 
to  the  peritoneal  surface.  No  action  is  observed  until  after 
an  interval  of  10  to  15  minutes  after  the  salt  solution  is 
placed  in  the  lumen  of  the  intestine,  while  application  of 
the  same  solution  to  the  peritoneal  surface  causes  move- 
ments of  the  intestine  within  one  minute. 

^' Log.  cit. 


CHAPTER  IV. 

The  Production  of  Increased  Secretion  of  Fluid 
into  the  Intestine  by  the  Saline  Purgatives. 

One  of  the  most  characteristic  things  to  be  observed  in 
purgation  is  the  presence  of  a  greater  quantity  of  fluid  in 
the  stools.  This  varies  in  degree  with  the  different  drugs, 
but  even  with  the  mild  laxatives  the  faeces  become  less  solid. 
With  the  stronger  purgatives  they  become  quite  fluid. 
Since  the  earliest  attempts  to  explain  the  nature  of  pur- 
gation there  has  been  the  question  as  to  the  origin  of  this 
fluid.  With  the  discovery  of  the  property  of  osmosis  in 
salts  a  new  life  was  given  to  this  inquiry,  and  Poiseuille^^ 
advanced  the  theory  that  the  purgative  effect  of  salts  was 
due  entirely  to  their  endosmotic  power,  the  increased  fluid 
of  the  faeces  being  caused  by  the  extraction  of  fluid  from 
the  tissues  by  the  osmotic  power  of  the  salt.  The  same 
view  was  held  by  Liebig,^*  whose  name  is  commonly  asso- 
ciated with  the  hypothesis.  Rabuteau^^  later  on  supported 
this  idea  and  claimed  as  proof  of  it  the  fact  that  he  was 
unable  to  produce  purgation  by  the  intravenous  injec- 
tion of  large  quantities  of  sodium  sulphate.  He  even 
found  that  this  injection  caused  constipation,  and  he  con- 
cluded that  since  sodium  sulphate  purges  when  given  by 
mouth  there  must  be  caused  a  flow  of  fluid  towards  the  salt 


^^  Eecherch.  experiment,  sur  les  mouvements  des  liquides  dans  les 
tubes  de  petits  diametres,  Paris,  1828.  Comptes  rendus  t.  19,  1844. 
Quoted  from  Hay. 

"*  tJber  die  Saf  tbewegung,  1848. 

'°L 'Union  Medicale,  1871,  Nos.  50  et  52.   Gaz.  Med.  de  Paris,  1879. 


30 


in  both  cases.  This  osmosis  theory  was  attacked  by  Claude 
Bernard,^*'  who  pointed  out  that  if  the  purgative  action  of 
salts  were  due  to  their  osmotic  power,  sugar  must  also  be  a 
strong  purgative.  He  found  further  that,  contrary  to  wh^t 
Rabuteau  stated,  intravenous  injections  of  sodium  sulphate 
do  cause  purgation  and  bring  it  about  more  rapidly  and 
powerfully  than  when  the  salt  is  taken  by  mouth.  It  was 
further  shown  by  Aubert^^  that  the  purgative  effect  of  va- 
rious salts  is  not  at  all  proportional  to  their  endosmotie 
power  nor  to  their  concentration.  Headland,^^  assuming 
without  experiment  that  purgative  salts  act  when  intro- 
duced into  the  circulation,  advanced  the  hypothesis  that 
when  they  are  given  by  mouth  they  are  first  absorbed  into 
the  blood  and  are  later  excreted  by  the  intestine.  In  thus 
passing  through  the  intestine  he  supposed  that  they  stimu- 
lated the  glands  to  secrete.  Brieger,^^  using  the  method  in- 
troduced by  Colin  and  Moreau,  obtained  what  he  considered 
an  increased  secretion  into  the  intestine.  Isolating  a  loop 
of  the  intestine,  he  introduced  into  it  a  strong  solution  of 
MgSO^.  The  loop  became  in  a  short  time  filled  with  a  clear 
yellow  alkaline  fluid.  This  he  believed  was  due  partly  to 
the  water  attracting  power  of  the  salt,  and  partly  to  the  pro- 
duction of  a  real  secretion.  Vulpian*°  believed  that  the  fluid 
was  due  to  an  inflammatory  irritation.  Hay*^  made  experi- 
ments similar  to  those  of  Brieger,  and  found  that  the  in- 
troduction into  a  loop  of  10%  NaaSO^  caused  a  considerable 
increase  in  the  secretion,  although  no  secretion  was  obtained 
by  a  1-5%  solution.  Schmiedeberg*-  explained  the  presence 
of  a  greater  quantity  of  fluid  in  the  stools  following  the 
administration  of  the  purgative  by  the  supposition  that  the 


^"  Lemons  sur  les  eff  ets  des  substances  toxiques  et  medieamenteuses, 
Paris,  1857. 

"  Zeitseh.  f.  Eationelle  Medicin,  Bd.  1,  1851. 

^^  Action  of  Medicines,  1857. 

=»  Archiv  f .  exp.  Path.  u.  Pharm.,  Bd.  VIII,  1878,  S.  355. 

^"  Gazette  Medicale,  1873. 

"  Journal  of  Physiology,  Vol.  XVI,  1882. 

*-  Arzneimittellehre,  Leipzig,  1883. 


31 


purgative  salts  on  reaching  the  large  intestine  prevent  the 
absorption  of  water.  He  states  that  these  salts  are  them- 
selves absorbed  with  diflBeulty  and  hence  reach  the  lower 
part  of  the  intestine  unchanged.  A  similar  hypothesis  is 
advanced  by  Wallace  and  Cushny.*^  They  stated  that  the 
absorption  of  fluid  was  inhibited  especially  by  those  salts 
which  form  insoluble  compounds  with  calcium.  These 
authors,  however,  did  not  take  into  account  the  possibility 
of  the  secretion  of  fluid  into  the  intestine  being  increased  by 
these  salts.  Hence  their  method  of  determining  the  differ- 
ence in  absorption  of  the  various  solutions  is  open  to  criti- 
cism, since  it  will  be  shown  in  this  chapter  that  some  if  not 
all  of  these  purgative  salts  cause  a  very  definite  increase  in 
the  intestinal  fluid.  The  absorption  of  fluid  may  indeed  be 
diminished  by  these  salts,  but  it  is  difficult  to  say  in  the 
experiments  of  Wallace  and  Cushny  how  much  of  the  fluid 
remaining  in  the  loops  is  due  to  inhibited  absorption,  and 
how  much  has  been  actually  secreted  by  the  intestine. 

The  experiments  of  Brieger**  and  Hay*^  in  the  produc- 
tion of  increased  secretion  are  quite  unsatisfactory  on  ac- 
count of  the  great  concentration  of  the  solutions  used. 
Their  results  may  well  be  ascribed  to  the  local  irritating 
effect  of  the  strong  solution,  since  they  did  not  obtain  an 
increased  secretion  with  weaker  solutions. 

As  stated  above  in  a  previous  section,  I  have  made  a 
large  number  of  experiments  to  determine  whether  or  not 
an  increased  secretion  is  actually  caused  by  the  saline  purg- 
atives, and  have  found  by  measurements  that  with  some  of 
the  salts  this  increase  is  very  marked.  These  results  have 
been  already  published,*®  and  the  tables  and  a  part  of  the 
description  given  below  are  taken  from  this  paper.  Rab- 
bits and  dogs  were  used  in  these  experiments.  In  the  case 
of  the  rabbits  anaesthesia  was  produced  by  the  subcuta- 

*^  Amer.  Journ.  Physiol.,  Vol.  I,  1898,  p.  411. 

**  Loc.  cit. 

^Loc.  cit. 

«  Amer.  Journ.  Physiol.,  Vol.  X,  1904,  p.  209. 


32 


neons  injection  of  4-5  e.e.  1%  morphine  hydrochlorate. 
The  rabbits  were  not  full  grown,  their  average  weight  being 
not  more  than  1,200  g.  The  same  amount  of  morphine  was 
given  also  to  the  dogs,  and  was  supplemented  by  ether.  The 
abdominal  cavity  was  opened  and  a  loop  of  considerable 
length  tied  off  with  ligatures'.  In  the  rabbit  the  upper  part 
of  the  small  intestine  was  selected  and  the  upper  ligature 
placed  just  below  the  entrance  of  the  common  bile  duct. 
The  second  ligature  was  tied  25  to  30  cm.  lower  down.  At 
the  lower  end  of  the  loop  a  large  mouthed  cannula  was  in- 
serted from  which  the  fluid  could  be  drained  by  gently  lift- 
ing the  successive  parts  of  the  loop,  a  process  made  more 
easy  by  placing  the  animal  board  at  a  considerable  angle 
with  the  table.  All  of  this  was  done  as  rapidly  as  possible, 
so  that  the  loops  would  be  exposed  as  little  as  possible  to 
the  air.  After  the  loop  had  been  emptied  of  what  it  con- 
tained in  this  way,  the  intestines  were  covered  over  with 
filter  paper  soaked  in  warm  m/6  NaCl  solution,  and  this 
again  covered  with  a  towel  wet  with  warm  water,  and  over 
it  all  a  woolen  cloth.  In  this  way  the  loops  were  protected 
fairly  well  from  drying  and  loss  of  heat.  The  contact  with 
the  wet  filter  paper  did  not  seem  in  any  way  to  affect  the 
intestine.  Other  experiments  were  made  with  the  filter 
paper  raised  from  the  intestine  by  a  wire  tent.  I  found 
that  if  these  precautions  against  loss  of  heat  and  drying 
were  neglected  the  secretion  did  not  take  place.  The  great- 
est care  must  be  exercised  in  this  respect  since  the  slightest 
cooling  seems  to  inhibit  the  secretory  activity  of  the  in- 
testine. 

The  loop  which  had  thus  been  emptied  and  returned  to 
moist  warm  surroundings  was  left  10  minutes  and  the  nor- 
mal secretion  allowed  to  collect,  and  at  the  end  of  that 
period  the  loop  was  again  emptied  with  as  little  exposure 
as  possible  and  the  fluid  measured.  The  cannula  was  then 
clamped  off  and  the  secretion  allowed  to  gather  for  a  second 
10  minutes.    This  again  was  drawn  off  and  measured.    The 


33 


quantity  secreted  was  usually  fairly  constant  and  quite 
small,  the  manipulation  undoubtedly  increasing  it  some- 
what. When  the  normal  secretion  was  obtained  the  purg- 
ative salt  in  an  isotonic  solution  was  administered  either 
subcutaneously,  intravenously,  or  locally.  The  secretion 
was  again  allowed  to  collect,  and  was  drained  off  and  meas- 
ured after  10  minutes.  This  was  repeated  several  times 
and  the  amounts  compared  with  what  was  taken  as  the 
normal  secretion.  When  the  solution  was  applied  locally, 
a  method  which  is  perhaps  the  most  satisfactory,  it  was 
allowed  to  drop  on  the  loops  from  a  pipette,  care  being 
taken  to  have  it  at  body  temperature  and  as  nearly  as  pos- 
sible isosmotic  with  the  blood.  In  each  case  special  care 
was  taken  to  have  no  interval  between  the  emptying  of  the 
loop  and  the  beginning  of  the  succeeding  period  of  10  min- 
utes. In  other  words,  the  loop  was  always  entirely  empty 
at  the  beginning  of  each  period. 

The  results  of  a  few  of  these  experiments  may  be  seen 
in  the  following  reports : — 

1.  Eabbit.    Loop  30  cm.  long,  upper  part  of  small  intestine. 

Loop  contained  in  beginning"    5.0  c.c. 

Fluid  removed  after  1st  10  minutes  0.2  c.c. 

Fluid  removed  after  2d    10  minutes  0.5  c.c. 

2  c.c.  m/8  BaCla  injected  subcutaneously. 

Fluid  removed  after  1st  10  minutes  following  injection  4.0  c.c. 

Fluid  removed  after  2d    10  minutes  following  injection  3.4  c.c. 

Fluid  removed  after  3d    10  minutes  following  injection  3.0  c.c. 

In  this  rabbit  the  increased  secretion  of  fluid  was  accom- 
panied by  extremely  active  peristaltic  movements.  The 
faeces  could  be  seen  passing  along  the  loops  of  the  lower 
part  of  the  intestine  with  great  rapidity.  Within  30  min- 
utes after  the  administration  of  the  salt,  the  passage  of 
faeces  to  the  outside  began.    This  continued  for  some  time, 

"  In  all  these  experiments  there  was  no  interval  beteen  the  empty- 
ing of  the  loop  and  the  beginning  of  the  10-minute  period  which  fol- 
lowed. The  injections  were  made  as  rapidly  as  possible,  and  in  no 
case  occupied  more  than  a  minute. 


34 


the  faeces  becoming  constantly  softer,  until  finally  they  were 
almost  entirely  unformed. 

As  shown  by  this  experiment,  and  also  by  the  following 
ones,  the  action  of  barium  chloride  persists  for  a  consider- 
able length  of  time.  The  action  of  sodium  citrate  is  more 
transitory. 

2.  Eabbit.     Loop  25  cm.  long. 

Loop    contained    in    be- 
ginning       3.0  c.c.  fluid  deeply  bile  stained 

After  1st  10  minutes....   1.0  c.c.  fluid  deeply  bile  stained 

After  2d    10  minutes....   0.8  c.c.  fluid  somewhat  lighter  in  color 
Injected  2  c.c.  m/8  BaClj  solution  subcutaneously. 

After   1st   10   min.   fol- 
lowing injection  2.5  c.c.  fluid  light  yellow 

After    2d    10   min.    fol- 
lowing injection  1.6  c.c.  fluid  very  light  yellow 

After    3d    10    min.    fol- 
lowing injection  1.8  c.c.  fluid  almost  colorless 

After  4th   10   min.   fol- 
lowing injection  1.6  c.c.  fluid  quite  colorless 

After   5th   10   min.   fol- 
lowing injection  1.0  c.c.  fluid  quite  colorless 

3.  Eabbit.     Loop  32  cm.  long. 

Loop  contained  in  beginning  6.0  c.c. 

After  1st  10  minutes  0.4  c.c. 

After  2d    10  minutes  0.1  c.c. 

After  3d    10  minutes  0.4  c.c. 

Poured  5  c.c.  m/8  sodium  citrate  on  loop. 

After  1st  10  minutes  6.2  c.c. 

After  2d    10  minutes  2.0  c.c. 

4.  Dog.     Loop  35  cm.  long. 

Loop  contained  no  fluid,  i.e.,  none  could  be  drained  off. 

After  1st  10  minutes  0.0  c.c. 

After  2d    10  minutes  0.0  c.c. 

After  3d    10  minutes  0.0  c.c. 

Poured  3  c.c.  m/8  BaClj  on  loop. 

After  1st  20  minutes  8.0  c.c. 

After  2d    20  minutes  0.6  c.c. 

Poured  li  c.c.  m/8  BaClj  on  loop  just  enough  to  moisten  it. 

After  1st  20  minutes  3.2  c.c. 

After  2d    20  minutes  2.5  c.c. 


35 


From  these  experiments,  in  which  every  precaution  was 
taken,  it  seems  certain  that  a  definite  increase  in  the  secre- 
tion of  fluid  into  the  intestine  follows  the  administration  of 
barium  chloride,  and  sodium  citrate,  the  former  of  which  is 
a  saline  purgative  of  a  more  powerful  type,  while  the  latter 
is  among  the  milder  purgative  salts.  It  is  of  especial  in- 
terest that  these  salts  do  not  produce  the  increase  of  fluid 
on  account  of  an  irritating  effect  on  the  mucous  membrane 
of  the  intestine.  The  action  takes  place,  as  shown  in  the 
experiments,  when  they  are  introduced  subcutaneously  or 
directly  applied  to  the  peritoneal  surface  of  the  intestine. 
Further,  the  solutions  were  practically  isosmotic  with  the 
blood,  and  for  this  reason  and  from  the  fact  that  they  were 
applied  to  the  peritoneal  surface  of  the  intestine  the  osmotic 
pressure  of  the  solution  could  play  no  part  in  causing  fluid 
to  enter  the  lumen  of  the  gut.  Also  it  is  obvious  that  any 
possible  effect  which  the  purgatives  may  have  in  delaying 
absorption  from  the  intestine  (Wallace  and  Cushny)  could 
have  nothing  to  do  with  the  production  of  this  increased 
amount  of  fluid  in  the  loops  experimented  with.  The  fluid 
produced  is  clear  and  either  colorless  or  slightly  yellow.  It 
has  an  alkaline  reaction  and  is  apparently  quite  similar  to 
the  normal  intestinal  secretion.  I  have  made  no  experi- 
ments to  determine  its  powers  of  digesting  and  have  no 
data  concerning  this  point.  There  are  no  signs  of  its  being 
of  an  inflammatory  nature. 

Thinking  that  the  manipulation  of  the  intestine  and  the 
tying  off  of  loops  might  influence  the  results,  I  estimated 
from  the  examination  of  a  large  number  of  rabbits  of  the 
same  size  (about  1,200  g.  in  weight)  the  quantity  of  fluid' 
which  is  normally  found  in  the  small  intestine.  It  was 
found  that  there  was  hardly  ever  more  than  10  c.c,  and 
usually  only  5  or  6  c.c.  of  fluid  in  addition  to  a  small 
amount  of  semifluid  food  material.  To  a  rabbit  in  which 
the  intestines  seemed  almost  empty,  a  small  dose  of  barium 
chloride  was  given  locally  by  pouring  an  m/8  solution  on  the 


36 

loops.  The  characteristic  effect  of  the  barium  followed,  and 
after  one  hour  the  small  intestine  was  tied  off  by  ligatures 
and  removed.  It  was  found  to  contain  22  c.e.  of  a  clear 
yellowish  fluid.  In  a  second  rabbit  which  received  the  same 
treatment  34  c.c.  of  a  similar  fluid  were  found  in  the  small 
intestine. 

As  will  be  shown  in  a  later  chapter,  a  secretion  of  fluid 
into  the  lumen  of  isolated  loops  of  intestine  removed  from 
the  body  may  be  produced  by  immersing  the  loops,  with 
their  ends  tied,  in  solutions  of  various  saline  purgatives. 
In  m/8  solutions  of  NaCl,  NajSO^,  and  sodium  citrate  no 
secretion  was  obtained  in  these  loops.  In  m/2  solution  of 
these  salts,  however,  a  distinct  measurable  quantity  was 
regularly  produced;  m/8  solutions  of  NaF  brought  about 
a  secretion,  and  in  all  solutions  containing  BaClg  a  distinct 
secretion  of  fluid  was  obtained.  This  will  be  described  in 
detail  later  on. 

As  stated  above,  Bottazzi  has  found  that  an  extract  of 
the  small  intestine,  which  increases  the  secretion  of  pan- 
creatic juice,  is  capable  also  when  injected  intravenously 
of  increasing  not  only  the  secretory  activity  of  the  intestine, 
but  also  its  peristalsis. 

As  stated  in  detail  in  another  chapter,  the  secretion  of 
fluid  into  the  intestine,  as  well  as  the  peristaltic  movements, 
is  inhibited  by  the  administration  of  calcium  or  magnesium 
chloride.  This  is  illustrated  by  the  following  experi- 
ments : — 
1.  Eabbit.     Loop  23  cm.  long. 

Loop  contained  in  beginning  0.9    c.c. 

Fluid  secreted  during  1st  10  minutes  0.7    c.c. 

Fluid  secreted  during  2d    10  minutes  0.6    c.c. 

2  c.c.  m/8  CaClj  applied  locally. 

Fluid  secreted  during  1st  10  minutes  0.15  c.c. 

Fluid  secreted  during  2d    10  minutes  0.0    c.c. 

Fluid  secreted  during  3d    10  minutes  0.0    c.e. 

4  c.c.  m/8  sodium  citrate  applied  locally. 

Fluid  secreted  during  1st  10  minutes  0.4    c.c. 

Fluid  secreted  during  2d    10  minutes  0,2    c.e. 


37 


2.  Eabbit.     Loop  25  cm.  long. 

Loop  contained  in  beginning  2.0    c.c. 

Fluid  secreted  during  1st  10  minutes  0.8    c.c. 

Fluid  secreted  during  2d    10  minutes  0.4    c.c. 

2  c.c.  m/8  CaClz  applied  locally  to  serous  surface. 

Fluid  secreted  during  1st  10  minutes  following  appli- 
cation      0.0    c.c. 

Fluid  secreted  during  2d  10  minutes  following  appli- 
cation      0.0    c.c. 

4  c.c.  m/8  sodium  citrate  applied  locally. 

Fluid  secreted  during  1st  10  minutes  0.6    c.c. 

3.  Eabbit.     Loop  22  cm.  long. 

Loop  contained  in  beginning  2.4    c.c. 

Fluid  secreted  during  1st  10  minutes  1.2    c.c. 

Fluid  secreted  during  2d    10  minutes  1.15  c.c. 

3  c.c.  m/8  MgClj  applied  locally  to  serous  surface. 

Fluid  secreted  during  1st  10  minutes  following  appli- 
cation     0.0    c.c. 

Fluid  secreted  during  2d  10  minutes  following  appli- 
cation     0.0    c.c. 

Fluid  secreted  during  3d  10  minutes  following  appli- 
cation      0.2    c.c. 

Although  in  these  experiments  the  quantity  of  fluid 
secreted  is  small,  there  is  a  definite  cessation  of  this  excre- 
tion following  the  application  of  calcium  or  magnesium 
chloride.  The  subsequent  administration  of  sodium  citrate 
in  each  case  causes  the  secretion  to  recommence. 


CHAPTER  V. 

The  Inhibiting  Action   of  Calcium   and  Magnesium  on 
the  Movements  and  Secretion  of  the  Intestine. 

It  was  first  observed  by  Ringer*®  that  the  unfavorable 
effect  produced  by  pure  NaCl  solution  could  be  lessened  by 
adding  other  salts,  notably  calcium  and  potassium.  From 
this  observation  there  was  made  the  so-called  Ringer's  solu- 
tion, which  contains  Na,  K,  and  Ca  in  proportions  which 
render  the  solution  relatively  neutral  and  innocuous  to- 
wards the  living  tissues. 

Howell,*®  working  with  the  heart  of  the  terrapin  in  va- 
rious mixtures  of  Na,  K,  and  Ca  chloride,  emphasized  the 
importance  of  calcium  in  the  medium  in  which  the  heart 
beat.  He  concluded  from  his  experiments  that  the  sodium 
chloride  was  mainly  instrumental  in  establishing  and  main- 
taining the  proper  osmotic  conditions,  while  calcium  was 
the  main  factor  in  initiating  and  maintaining  the  beat  of 
the  heart.  To  quote  from  his  articles : — ' '  The  stimulus  that 
leads  to  a  heart  contraction  is  dependent  upon  the  presence 
of  calcium  compounds  in  the  liquids  of  the  heart;  but  for 
rhythmic  contractions  and  relaxations  a  certain  proportion 
of  potassium  compounds  is  necessary. "  "  The  sodium  chlo- 
ride seems  to  be  essential  only  in  preserving  the  osmotic  re- 
lations between  the  tissues  and  the  surrounding  liquid." 
Similar  conclusions  were  arrived  at  by  Green.^° 

'^  Journal  of  Physiology,  Vols.  4,  5,  6,  8,  16,  17,  and  18,  1883-1895. 
«  Amer.  Journ.  Physiol.,  Vol.  2,  1898,  p.  47. 
'"  Amer.  Journ.  Physiol.,  Vol.  2,  1898,  p.  82. 


39 


Loeb,^^  working  with  Gonionemus,  and  with  the  stri- 
ated muscles  of  the  frog,  arrived  at  conclusions  which  are 
in  some  respects  entirely  opposed  to  those  of  Howell.  What 
Loeb  spoke  of  as  the  toxic  effects  of  sodium  chloride  was 
emphasized  by  this  work.  This  was  especially  shown  in  the 
case  of  Fundulus  eggs  which,  though  freshly  fertilized,  can- 
not develop  in  pure  NaCl  solution,  although  they  develop 
in  sea-water  or  in  distilled  water.  In  this  case  the  addition 
of  a  small  quantity  of  calcium  chloride  to  the  NaCl  ren- 
dered development  possible.  According  to  Loeb,  the  Ca 
exerted  an  antitoxic  effect  and  neutralized  the  injurious 
action  of  the  NaCl.  Similarly  it  was  found  that  the  apex 
of  the  heart  contracts  rhythmically  in  a  pure  NaCl  solution, 
but  soon  came  to  a  standstill.  The  addition  of  a  small 
amount  of  calcium  is  sufficient  to  cause  the  contractions  to 
persist  for  a  long  time.  This  again  was  referred  to  the 
toxic  and  antitoxic  effects  of  the  salts.  From  these  and 
similar  experiments  arose  the  conception  of  "physiologi- 
cally balanced  solutions"  in  which  the  toxic  effect  of  each 
substance  in  the  solution  is  exactly  counteracted  by  the  anti- 
toxic effect  of  some  other  substance  in  the  same  solution. 

Other  experiments  by  Loeb  showed  that  if  the  volun- 
tary muscle  of  a  frog  be  immersed  in  a  pure  NaCl  solution, 
rhythmical  twitchings  appear  which  continue  for  many 
hours,  or  even  for  days.  If,  however,  a  small  quantity  of 
CaClg  be  added  to  the  NaCl  solution  the  twitchings  cease, 
although  the  muscle  remains  alive  in  this  mixture  longer 
than  it  does  in  pure  NaCl.  Similar  results  were  obtained 
with  solutions  of  the  sodium  salts  which  precipitate  cal- 
cium, fluoride,  oxalate,  carbonate,  phosphate,  etc.  In  all 
of  these  solutions  twitchings  developed  in  the  muscle.  Mag- 
nesium and  strontium  act  like  calcium  in  inhibiting  the 
muscular  twitchings  produced  by  sodium  salts.  These  ex- 
periments led  Loeb  to  the  conclusion  that  the  presence  of 

"^  Festschrift  f .  Fick,  1899.  Chicago  Decennial  Publications,  1902, 
and  Pfliiger's  Archiv,  Bd.  91,  S.  248,  1902.  Amer.  Journ.  Physiol., 
Vol.  5,  1901. 


40 


calcmm  in  the  body  keeps  the  voluntary  muscles  from  con- 
stantly twitching  or  beating  rhythmically  in  the  way  the 
heart  does.  Calcium,  magnesium,  and  strontium  seemed  to 
have  a  definite  inhibitory  action  on  the  muscular  contrac- 
tions. -     • 

Loeb  further  showed  that  the  center  of  a  jellyfish  (Go- 
nionemus),  which  when  isolated  from  the  margin  will  not 
contract  in  sea-water,  will  beat  rhythmically  if  placed  in 
pure  NaCl  solution.  If  a  quantity  of  CaCla  or  Ca(N03)2 
be  added  to  the  NaCl  solution  the  contractions  are  inhib- 
ited. Magnesium  and  strontium  behave  in  this  respect  like 
calcium.  If  also  a  sufficient  quantity  of  a  calcium  precipi- 
tating solution  (sodium  fluoride,  phosphate,  etc.)  be  added 
to  sea-water  in  which  the  center  will  not  beat,  rhythmical 
contractions  soon  appear,  due  apparently  to  the  removal  of 
the  calcium  from  the  sea-water  and  the  tissue.  In  these  ex- 
periments, as  in  those  with  voluntary  muscles,  calcium  mag- 
nesium and  strontium  have  apparently  an  inhibiting  action 
on  muscular  contractions. 

Loeb  has  recently  made  experiments  on  a  jellyfish  of 
the  Pacific  (Poly orchis)  with  results  which  are  somewhat 
different  from  those  described  for  voluntary  muscles  and 
Gonionemus.  He  found  that  the  normal  swimming  move- 
ments of  the  uninjured  animal  could  not  occur  in  solutions 
which  did  not  contain  some  proportion  of  magnesium,  and 
the  presence  of  magnesium  in  the  sea-water  seemed  to  be 
the  stimulus  for  the  apparently  spontaneous  movements  of 
the  animal.  Calcium  and  potassium  were  found  to  oppose 
this  action  of  magnesium.  Further  with  the  isolated  center 
of  Polyorchis,  which  will  not  beat  in  pure  sugar  solution  or 
in  sea-water,  it  was  found  that  the  addition  of  CaClo,  SrCL, 
or  BaClg  to  either  solution  caused  contractions  to  appear. 
Magnesium  chloride  did  not  produce  this  effect.  In  pure 
NaCl  solution  also  the  isolated  center  will  not  beat,  or  beats 
only  after  a  long  time,  while  the  addition  of  CaClg  to  the 
NaCl  causes  it  to  beat  at  once. 


41 

Lingle^-  made  experiments  with  the  ventricle  of  the  tor- 
toise heart,  which  was  able  to  beat  for  only  a  short  time  in 
pure  NaCl  solutions.  When  a  small  amount  of  CaClg  is 
added,  however,  the  heart  may  continue  to  beat  for  a  long 
period.  Lingle  explained  this  by  the  assumption  that  NaCl 
is  a  poison  and  that  calcium  acts  in  an  antitoxic  way,  a  sug- 
gestion already  offered  by  Loeb. 

Loeb  's  experiments  on  the  inhibition  of  muscular  twitch- 
ings  in  voluntary  muscles  by  calcium  and  magnesium,  as 
well  as  the  similar  results  he  obtained  with  the  isolated 
center  of  Gronionemus,  led  me  to  test  the  action  of  these  two 
substances  on  the  rhythmical  movements  of  the  mammalian 
intestine.  It  was  found  that  not  only  the  normal  move- 
ments of  the  intestine,  but  also  those  produced  by  the  saline 
purgatives  such  as  sodium  citrate,  sulphate,  tartrate,  etc., 
could  be  very  definitely  inhibited  by  the  administration  of 
calcium  or  magnesium  chloride.  This  was  the  case  when 
these  latter  substances  were  given  in  any  way  either  intra- 
venously, subcutaneously,  or  applied  directly  to  the  serous 
surfaces  of  the  intestine.  The  following  experiments  will 
illustrate  this  inhibitory  action. 

A  rabbit  was  anaesthetized  by  a  subcutaneous  injection 
of  4—5  c.c.  1%  morphine  solution.  The  intestines  were  then 
carefully  exposed  and  protected  in  every  way  from  loss  of 
heat  and  moisture.  The  method  suggested  by  van  Braam- 
Houckgeest"^  of  opening  the  abdomen  under  the  surface  of 
sodium  chloride  solution  is  perhaps  the  most  perfect.  A 
small  quantity  of  m/6  sodium  citrate  solution  (for  a  rabbit 
weighing  1,200  g.  2-3  c.c.  is  sufficient)  was  injected  into  a 
vein  of  the  ear.  The  intestines  almost  immediately  began 
to  move  actively.  There  was  then  injected  3-4  c.c.  m/6 
CaClg  solution.  The  intestines  within  2  or  3  minutes  came 
entirely  to  rest  and  remained  perfectly  quiet.  A  second 
injection  of  a  somewhat  greater  quantity  of  sodium  citrate 
caused  them  to  again  become  active. 

=2Amer.  Journ.  Physiol.,  Vol.  4,  p.  265,  1900;  Vol.  8,  p.  75,  1902. 
^^'Pfliiger's  ArcMv,  Bd.  6,  1872;  and  Bd.  8,  1874. 


42 


A  still  more  striking  experiment  may  be  made  by  expos- 
ing the  intestines  and  pouring  a  small  quantity  of  sodium 
citrate  solution  on  their  peritoneal  surfaces.  Immediately 
they  become  extremely  active.  If  now  they  be  washed  off 
with  a  little  NaCl  solution  and  a  few  c.e.  of  a  solution  of 
calcium  chloride  be  poured  on  them  they  will  come  to  rest 
at  once.  These  solutions  must  be  at  body  temperature  and 
isotonic  with  the  blood.  If  the  loops  which  have  been 
quieted  by  CaClg  are  again  moistened  with  the  citrate  solu- 
tion they  will  be  set  into  motion  as  before,  and  a  subsequent 
application  of  CaClg  will  again  cause  all  movement  to  cease. 
This  may  be  continued  almost  indefinitely.  I  have  set  the 
same  loops  in  motion  and  stopped  them  by  these  solutions  as 
many  as  sixteen  times  in  succession. 

Magnesium  chloride  acts  in  this  respect  like  calcium 
chloride,  and  a  similar  but  slighter  action  is  possessed  by 
strontium  chloride.  Magnesium  sulphate  has  a  purgative 
action  just  as  many  other  sulphates  have.  Magnesium  cit- 
rate also  acts  in  the  same  way  as  other  citrates.  The  action 
of  the  magnesium  in  these  cases  seems  to  be  subordinate. 

In  addition  to  the  inhibitory  action  of  calcium  and  mag- 
nesium on  the  peristaltic  movements  of  the  intestine,  these 
substances  also  suppress  the  secretion  of  fluid  into  the  in- 
testine. This  is  shown  in  the  previous  chapter  (IV),  where 
tables  are  given  to  show  the  course  of  the  experiments.  Ac- 
cording to  these  experiments,  the  normal  rate  of  secretion 
in  an  isolated  loop  was  measured.  The  quantity  of  fluid 
secreted  was  small,  but  the  application  of  CaClg  or  MgClg 
to  the  serous  surface  of  the  loop  stopped  the  secretion  en- 
tirely. The  subsequent  application  of  sodium  citrate  caused 
it  to  flow  again. 

In  its  counteraction  of  the  effect  of  saline  purgatives, 
calcium  behaves  in  the  same  way.  The  increased  peristalsis 
or  secretion  caused  by  sodium  citrate,  sulphate,  etc.,  is  en- 
tirely suppressed  by  the  administration  of  calcium  or  mag- 
nesium chloride.     This  is  not  true  to  the  same  extent  of 


43 


those  activities  produced  by  barium  chloride.  CaCla  as  far 
as  I  have  been  able  to  determine  only  partially  counteracts 
the  effect  of  BaCla-  That  an  antagonism  does  exist  cannot 
be  doubted,  but  the  violent  peristaltic  movements  brought 
about  by  BaCla  cannot  be  fully  suppressed  by  CaCla  or 
MgCl,.  As  mentioned  above,  BaClg  in  extremely  small 
doses  causes  an  increased  flow  of  urine.^*  This  can  be  par- 
tially inhibited  by  CaCla-  With  slightly  larger  doses  of 
barium,  the  flow  of  urine  often  ceases  abruptly,  due  prob- 
ably to  the  contraction  of  the  musculature  of  the  urinary 
passages,  or  possibly  to  a  contraction  of  the  blood  vessels 
of  the  kidney.  This  condition  is  relieved  by  the  adminis- 
tration of  CaCla,  that  is,  the  calcium  merely  counteracts  the 
effect  of  the  barium  on  the  musculature  of  the  urinary  pas- 
sages or  blood  vessels,  whichever  it  may  be. 

Experiments  have  recently  been  made  to  test  the  effect 
of  adding  calcium  salts  to  barium  chloride  and  feeding  the 
two  mixed  with  some  edible  substance  to  mice.  BaClg  is  a 
common  poison  to  employ  for  mice  and  rats.  It  was  found 
that  the  mice  eating  food  containing  barium  carbonate 
alone  died,  while  those  eating  the  mixture  of  calcium  car- 
bonate and  barium  carbonate  in  the  food  were  unharmed.^^ 

"When  loops  of  the  intestine  are  entirely  removed  from 
the  body  and  placed  in  sodium  chloride  solution,  active 
movements  begin,  as  will  be  described  in  detail  in  a  later 
chapter.  These  movements  continue  40  to  45  minutes  or 
longer  if  the  proper  conditions  of  temperature,  etc.,  are 
preserved.  If,  however,  CaCla  be  added  to  this  solution  the 
movements  are  inhibited.  Also  loops  placed  in  pure  m/6 
CaClo  solution  lie  perfectly  quiet. 

A  peculiar  action  of  calcium  which  will  be  described  in 
detail  later  on  is  shown  in  the  following  experiments:  A 
loop  of  rabbit's  intestine  was  removed  from  the  body  and 

"  MacCallum,  J.  B. :  Journal  exp.  Zoology,  No.  1,  1905. 
==  Stover,  P.  H. :  Bulletin  of  Bussey  Institution,  Vol.  II,  Part  IV, 
1884. 


44 


placed  in  a  solution  of  m/6  LiCl.  After  moving  rhythmic- 
ally for  about  15  seconds  the  loop  came  to  rest.  A  loop 
similarly  placed  in  m/6  CaCla  solution  showed  no  move- 
ments. In  a  mixture,  however,  of  50  c.c.  m/6  LiCl  -|-  5  c.c. 
m/6  CaClg  the  initial  movements  seen  in  the  pure  LiCl  so- 
lution were  absent  and  the  loop  remained  quiet  for  10-15 
minutes.  Then  sudden  sharp  constrictions  appear  in  the 
loop,  followed  by  violent  contractions  of  the  whole  loop. 
The  loop  twists  and  coils  upon  itself  and  continues  to  move 
in  this  extremely  active  manner  for  30-45  minutes  or 
longer.  The  control  loops  in  pure  LiCl  and  pure  CaCL  re- 
main motionless  during  all  this  time. 

A  similar  phenomenon  occurs  with  a  mixture  of  NaCl 
and  CaClg.  In  NaCl,  however,  the  initial  movements  are 
much  more  conspicuous  and  may  continue  for  an  hour. 
These  are  inhibited  in  the  mixture  of  NaCl  and  CaCL,  and 
after  10-15  minutes  movements  of  an  entirely  different 
character  appear,  resembling  those  described  for  mixtures 
of  LiCl  and  CaClg.  Sharp  constrictions  and  violent  twist- 
ings  persist  for  30  or  40  minutes. 

These  peculiar  contractions  do  not  occur  in  mixtures  of 
LiCl  and  NaCl,  nor  in  mixtures  of  CaClg  and  MgClg. 

In  addition  to  their  action  on  the  intestine,  calcium  and 
magnesium  have  a  very  definite  action  on  other  organs  of 
the  body,  more  especially  the  kidney.  It  was  found^®  that 
both  calcium  and  magnesium  chlorides  inhibit  the  flow  of 
urine.  This  is  shown  in  the  following  tables  taken  from  the 
paper  referred  to. 


="  MacCallum,  J.  B. :  Journal  Exp.  Zoology,  Vol.  I,  No.  1,  1904. 


45 


Rabbit — cannula  placed  in  bladder.  No  urine  flowed  in 
the  first  or  second  periods  of  10  minutes  before  the  NaCl 
solution  was  injected. 

„.  Salts  other  than  in/6  NaCl  Urine 

^^^^  NaOl  injected  injected  in  c.c.  inc.c. 

10:10                       10 

10:15                      10 

10:20                     5                      0.5 

10:40                     10                       0.8 

11:00                     10                      0.5 

11:20                      5                       1.0 

11:40                     10                      2.8 

12:00                     10                      6.0 

12:00  5  c.c.  m/6  CaCL 

intravenously 
12:05  5  c.c.  5m/6  CaCL 

subcutaneously 

12:20                     5                      0.2 

12:40                     10                       1.8 

1:00                     10                      0.8 

1 :  00  5  c.c.  m/6  sodium  cit- 

rate intravenously 

1:20                     10                      2.2 

1:40                     5                     3.6 

In  this  case,  although  the  flow  of  urine  was  consider- 
ably increased  by  the  injection  of  NaCl  solution,  and  al- 
though the  injection  was  continued,  the  introduction  of 
CaClg  caused  the  flow  to  almost  cease.  This  action  was 
quite  constant  and  was  obtained  in  a  large  number  of  ex- 
periments. MgCla  has  a  similar  but  less  powerful  effect. 
The  action  of  the  CaClg  is  temporary  and  wears  off  after  a 
little  time,  as  shown  in  the  following  table  taken  from  the 
same  paper.  It  represents  only  the  latter  half  of  the  ex- 
periment, the  regular  injection  of  2  c.c.  NaCl  solution  per 
minute  gradually  increasing  the  rate  of  flow  as  shown,  until 
the  quantity  of  fluid  excreted  almost  equals  that  injected. 


46 
Rabbit — cannula  in  bladder — injections  intravenous. 


Time 
9:25 

Salts 
Na 

5  c.c. 

other  than 
Jl injected 

in/6  NaCl 
injected  in  c.e. 

150 
10 
10 
10 
10 
10 

5 
10 
10 
10 
10 

8 

5 

0 

0 

0 

Urine 
ine.c. 

11:40 

64,5 

11:45 

6.6 

11:50 

5.6 

11:55 

6.2 

12:00 

7.4 

12:05 

•      9.5 

12:05 
12:10 

m/6  CaClj 

2.2 

12:15 

0.8 

12:20 

1.2 

12:25 

1.6 

12:30 

2.8 

12:35 

3.0 

12:40 

4.5 

12:45 

4.8 

12:50 

5.1 

12:55 

6.2 

It  was  found  in  another  series  of  experiments^^  that  the 
haemoglobinuria  caused  by  saponin  and  by  quillain,  which 
is  a  dried  extract  of  Quillaja  bark,  may  be  inhibited  by 
calcium  chloride.  The  intravenous  injection  of  2  c.c.  l^% 
quillain  always  produced  haemoglobinuria  in  a  rabbit 
weighing  about  1,200  g.  If  the  dilution  of  the  quillain 
were  made  with  m/6  CaClg  instead  of  water,  e.g.,  2  c.c.  1% 
quillain  -\-  6  c.c.  m/6  CaClg  and  2  c.c.  of  this  injected  in- 
travenously, no  haemoglobinuria  resulted,  although  the  con- 
centration of  the  quillain  was  the  same  in  both  cases.  The 
CaCla  does  not  stop  the  excretion  of  the  haemoglobin  by 
the  kidneys,  for  if  the  saponin  or  quillain  be  given  first  and 
the  haemoglobinuria  established,  the  subsequent  injection 
of  CaCla  does  not  stop  the  excretion  of  haemoglobin.  This 
is  explained  by  a  large  number  of  experiments  in  which  it 
was  shown  that  the  haemolysis  caused  by  saponin,  quillain, 
or  digitalin  is  particularly  inhibited  by  calcium  chloride 
and  magnesium  chloride.    This  can  be  seen  in  the  following 

"  MacCallum,  J.  B. :  University  of  California  Publications,  Phys- 
iology, Vol.  II,  1905,  p.  93. 


47 


table  in  which  defibrinated  rabbit's  blood  is  used,  and  the 
effects  of  CaCL  and  MgClg  are  compared  with  that  of  NaCl. 


Time 

A.M. 

1  c.c.  blood                           1  c.c.  blood 

5  e.e.  in/6  NaCl                  5  c.c.  m/6  MgClo 

3  drops  0.5?i  saponin            3  drops  0.5*'  saponir 

1  c.c.  blood 
5  c.c.  m/6  CaCl2 
I        3  drops  0.5^  saponin 

10:22 

10:24 

change  of  color 

no  change 

no  change 

10:27 

almost  transparent 

no  change 

no  change 

10:30 

laking  almost  complete 

;  no  change 

no  change 

10:45 

laking  complete 

no  change 

no  change 

P.M. 

1:00 

laking  complete 

corpuscles  settled    same  as  MgCl2 
to  bottom;   su-         mixture 
pernatant  fluid 
colored;   mixture 
quite  opaque  on 
shaking 

It 

is  of  considerable 

interest  to 

note  that  these  sub 

stances,  saponin,  quillain,  and  digitalin,  act  not  only  as 
haemolytics,  but  also  as  diuretics.  This  was  shown  in  a 
number  of  experiments.^^  As  shown  in  the  following  table, 
the  injection  of  a  very  small  quantity  of  saponin  produces 
a  distinct  increase  in  the  quantity  of  urine  excreted. 


Time 

m/6  NaCl  injected 
intravenously 

Urine 

10:15 

10:20 

10  c.c. 

2     c.c. 

10:25 

20  c.c. 

4     c.c. 

10:30 

20  c.c. 

6     c.c. 

10:35 

10  c.c. 

7.5  c.c. 

10:40 

10  CO. 

8.0  c.c. 

10:45 

10  c.c. 

8.2  c.c. 

10:50 

10  c.c. 

7.9  c.c. 

10:56 

Injected 

2  c.c.  1/20%  saponin  in 

m/6  NaCl 

11:00 

10  e.c. 

10.5  e.c. 

11:05 

10  c.c. 

11.0  c.c. 

11:10 

10  c.c. 

11.0  c.c. 

11:15 

10  c.c. 

11.0  c.c. 

11:16 

Injected 

1  c.c.  1/20%  saponin 

11:20 

10  c.c. 

12.2  c.c. 

11:25 

10  c.c. 

13.2  c.c. 

11:30 

10  c.c. 

12.0  c.c. 

11:35 

10  c.c. 

12.5  c.c. 

°*  MacCallum,  J.  B. :  Loc.  cit. 


48 


It  is  possible  that  it  is  by  no  means  a  coincidence  that 
these  substances  which  are  powerful  haemplytics  act  also 
as  diuretics;  and  that  CaClg  and  MgClg,  which  inhibit  the 
secretion  of  urine,  also  to  some  extent  inhibit  the  haemolytic 
action.  It  is  difficult  to  say  by  what  process  the  haemoglo- 
bin is  liberated  from  the  red  blood  corpuscle,  as  indeed  it 
is  difficult  to  state  definitely  how  fluid  passes  from  the  blood 
into  the  urine.  It  is  sufficient  to  call  attention  to  the  fact 
that  the  liberation  of  haemoglobin  and  the  flow  of  urine 
may  be  to  some  extent  controlled  by  the  same  conditions. 
If  the  haemolytics  such  as  saponin  cause  haemolysis  by  in- 
creasing the  permeability  of  the  membranes  of  the  red 
blood  corpuscles,  it  seems  possible  that  the  diuretic  effect 
of  these  substances  may  be  due  to  a  similar  process  in  the 
kidney.  If  this  be  true,  changes  in  permeability  must  play 
an  important  part  in  the  action  of  these  diuretics.  And  it 
is  not  impossible  that  the  inhibition  of  the  haemolytic  action 
of  saponin,  etc.,  as  well  as  the  inhibition  of  the  flow  of  urine 
by  CaCla  and  MgClg,  may  be  due  to  a  decreased  permeability 
of  the  red  blood  corpuscle  on  the  one  hand,  and  of  the  kid- 
ney cells  on  the  other. 

With  these  numerous  experiments  with  calcium  and 
magnesium  it  is  still  impossible  to  make  a  general  state- 
ment as  to  the  nature  of  their  action.  Since  the  chemical 
conditions  existing  in  the  tissues  of  animals  and  of  various 
parts  of  animals  are  largely  a  matter  of  conjecture,  we  can- 
not predict  how  these  substances  will  act ;  nor  can  we  say 
that  because  calcium,  for  example,  has  a  certain  action  in 
one  animal  or  on  one  organ  it  will  necessarily  have  the  same 
action  in  other  animals  or  in  other  organs. 

In  the  experiments  on  the  rabbit's  intestine,  however, 
calcium  and  magnesium  have  been  shown  to  have  an  action 
which  can  only  be  described  as  inhibitory.  In  an  animal 
as  highly  organized  as  the  rabbit,  the  intestine  is  an  ex- 
tremely complex  organ;  it  is  not  only  a  muscular  and  a 
glandular  organ,  but  contains  a  complicated  nervous  mech- 


49 


anism  peculiar  to  itself  which  is  entirely  inseparable  from 
the  other  parts.  It  is  not  possible  here  to  mechanically 
isolate  a  part  which  shall  be  free  from  the  nervous  system 
as  can  be  done  almost  completely  in  the  center  of  the  jelly- 
fish and  the  apex  of  the  heart.  We  are  dealing  with  an 
entire  organ  which  must  be  considered  as  an  indicator  by 
which  comparative  results  may  be  obtained.  So  many  un- 
known conditions  exist  in  such  an  organ  that  it  is  impossible 
to  say  what  tissue  is  acted  on  primarily,  whether  the  nerv- 
ous system  on  the  one  hand,  or  the  glandular  and  muscular 
tissues  on  the  other.  There  are,  however,  two  indicators  in 
the  intestine  by  which  the  comparative  actions  of  substances 
can  be  studied,  namely,  the  muscular  movements,  and  the 
secretion  of  fluid,  both  of  which  by  various  chemical  sub- 
stances may  be  increased  or  lessened;  or,  in  other  words, 
they  may  be  stimulated  or  inhibited.  These  terms  are  en- 
tirely comparative.  The  fact  that  calcium  and  magnesium 
act  as  inhibitors  for  both  the  muscular  and  secretory  activ- 
ities of  the  intestine  does  not  imply  that  they  have  a  similar 
action  in  other  organs  or  in  all  animals.  It  can  only  be 
said  with  certainty  that  the  chemical  conditions  under 
which  the  intestines  of  the  rabbit  live  are  fairly  constant, 
so  that  the  addition  of  calcium  or  magnesium  in  some  way 
constantly  inhibits  the  activity  of  both  muscular  and  glan- 
dular tissues,  and  the  addition  of  certain  purgative  salts 
constantly  stimulates  them  to  greater  activity. 


CHAPTER  VI.  -     ' 

The  Action  of  Saline  Solutions  on  Loops  of  Intestine 
Removed  from  the  Body. 

The  fact  shown  above  that  local  application  of  saline 
solutions  to  the  peritoneal  surfaces  of  the  intestine  could 
call  forth  not  only  muscular  movements  of  the  intestine, 
but  also  an  increased  secretion,  suggested  the  possibility  of 
experimenting  with  loops  of  intestine  entirely  removed 
from  the  body.  Loops  thus  isolated  are  necessarily  placed 
under  new  conditions  differing  entirely  from  those  under 
which  loops  normally  connected  exist.  As  mentioned  in  an 
early  chapter,  it  was  stated  by  Claude  Bernard  that  section 
of  the  spinal  cord  below  the  phrenic  causes  active  move- 
ments to  appear  in  the  intestine ;  and  it  was  later  shown  by 
Pfliiger  that  section  of  the  splanchnic  nerves  has  the  same 
effect,  and  stimulation  of  the  peripheral  cut  ends  caused 
the  movements  to  cease.  It  was  also  noticed  by  van  Braam- 
Houckgeest  that  although  loops  of  the  intestine  normally 
connected  in  the  body  remained  at  rest  when  immersed  in 
isotonic  NaCl  solution,  active  movements  appear  in  the 
loops  when  the  splanchnic  nerves  are  cut.  Moreau  further 
showed  that  section  of  the  mesenteric  nerves  causes  a  large 
increase  in  the  fluid  secreted  into  the  intestine. 

I  have  confirmed  these  results  and  have  found  that  loops 
which  are  quiet  when  the  abdomen  is  opened  remain  quiet 
when  placed  in  m/6  NaCl  solution.  If,  however,  loops  have 
become  active  in  any  way,  through  exposure  to  the  air,  or 
through  any  stimulation,  these  movements  continue  when 
the  loops  are  placed  in  the  salt  solution.  In  any  case  sec- 
tion of  the  cervical  cord  or  of  the  splanchnic  nerves,  or 


51 


clamping  of  the  nerves  and  bloodvessels  supplying  the  loops, 
causes  a  very  marked  increase  in  the  peristaltic  activity  of 
the  loops.  In  studying  the  behavior  of  isolated  loops  re- 
moved from  the  body  and  placed  in  various  solutions  it  was 
therefore  necessary  to  consider  the  effects  produced  by  the 
removal  itself. 

In  describing  these  experiments,  which  were  made  some 
time  ago,^''  a  word  may  be  said  as  to  the  methods  employed. 
The  rabbits  were  anaesthetized  with  morphine  as  described 
before ;  the  abdominal  cavity  was  opened  and  the  bloodves- 
sels supplying  the  loop  selected  were  carefully  tied  off. 
Two  pairs  of  ligatures  were  then  placed  around  the  intes- 
tine so  that  the  loop  was  properly  isolated.  The  intestine 
was  then  cut  between  each  pair  of  ligatures,  and  the  mesen- 
tery divided  between  the  bloodvessel  ligatures  and  the  in- 
testine. In  this  way  the  loop  could  be  taken  from  the  body 
without  injuring  it,  and  without  causing  the  animal  to  lose 
more  than  a  drop  or  two  of  blood.  The  loop  was  then  emp- 
tied by  cutting  one  ligature  and  allowing  the  fluid  to  drain 
from  that  end  while  it  was  held  up  by  the  ligature  of  the 
other  end.  The  open  end  was  then  religatured,  and  the 
whole  loop  suspended  in  the  solution  to  be  tested.  This  was 
arranged  so  that  both  ends  of  the  loop  were  above  the  sur- 
face of  the  solution,  in  order  that  none  of  the  solution  could 
by  any  possibility  enter  the  lumen  of  the  loop  through  the 
ligatured  ends.  The  beakers  containing  the  solutions  were 
kept  in  a  water  bath  at  39.5°  C.  The  movements  of  the  loops 
could  in  this  way  be  directly  watched,  and  the  amount  of 
fluid  secreted  in  a  unit  of  time  could  be  easily  measured. 

If  a  loop  such  as  has  been  described  above  be  removed, 
from  the  intestine  of  a  rabbit  and  placed  in   m/8-m/6 
NaCl  solution  at  body  temperature,  active  movements  at 
once  appear.     These  are  regular  and  rhythmical,  resem- 
bling those  which  set  in  when  the  nerves  to  the  intestine 

=°  MacCallum,  J.  B. :  University  of  California  Publications,  Phys- 
iology, Vol.  I,  1904,  p.  115, 


52 


are  cut  in  the  uninjured  animal.  If  the  loop  be  allowed  to 
lie  at  the  bottom  of  the  solution,  it  will  twist  and  writhe 
about  in  a  peculiar  worm-like  manner.  These  movements 
persist  in  varying  intensity  for  a  considerable  time,  some- 
times as  long  as  an  hour,  usually  for  40-45  minutes.-  They 
disappear  gradually.  No  attempt  was  made  to  obtain  a 
fluid  in  which  the  movements  could  be  maintained  for  a 
longer  time.  These  movements  are  probably  merely  the 
continuation  of  those  always  caused  by  sectioning  the 
nerves  to  the  loop.  The  m/6  or  m/8  NaCl  solution  seems 
to  be  fairly  favorable  for  their  maintenance.  That  the 
loop,  however,  is  not  dead  when  the  movements  in  NaCl 
cease  is  shown  by  the  fact  that  it  can  be  caused  to  exhibit 
active  movements  by  transferring  it  to  a  solution  of  NaCl 
containing  a  small  quantity  of  BaCl,.  It  is  of  course  not 
possible  to  say  that  the  movements  which  appear  when  the 
loop  is  placed  in  pure  NaCl  solution  are  entirely  due  to  the 
cutting  of  the  nerves  to  the  loop.  It  is  possible  that  the 
NaCl  acts  as  a  direct  stimulus  and  causes  the  movements  to 
continue. 

When  a  loop  is  carefully  emptied  and  suspended  in  a 
solution  of  m/8-m/6  NaCl  in  the  way  described,  it  is 
found  that  after  a  considerable  time  (20-40  minutes)  it  is 
still  quite  empty.  If,  on  the  other  hand,  an  m/2  solution  of 
NaCl  is  used  the  loop  is  found  to  contain  after  15  to  20 
minutes  a  small  but  distinct  quantity  of  clear  yellowish 
fluid  resembling  the  normal  intestinal  juice.  A  loop  27  cm. 
long  suspended  in  m/2  NaCl  for  20  minutes  contained  0.6 
c.c.  fluid.  A  second  loop  30  cm.  long  in  the  same  solution 
contained  0.8  c.c.  fluid.  A  control  loop  of  the  same  length 
in  m/8  NaCl  remained  empty.  In  m/2  NaCl  the  move- 
ments of  the  loop  are  spasmodic  and  the  contractions  very 
strong.  The  movements  do  not  usually  last  more  than  5 
minutes,  although  the  loop  may  be  removed  from  this  solu- 
tion 15  minutes  after  the  movements  have  ceased,  and  may 
be  caused  to  move  again  by  immersing  it  in  m/8  NaCl  con- 


53 


taining  1/25  of  its  volume  of  m/8  BaCL.  This  shows  that 
the  loop  is  not  actually  killed  by  the  strong  NaCl  solution. 

A  loop  suspended  in  m/6  sodium  citrate  solution  showed 
active  peristaltic  movements,  lasting  for  20  to  30  minutes. 
No  fluid,  however,  collected  in  this  loop.  When  suspended, 
however,  in  m/2  sodium  citrate  a  measurable  quantity  of 
fluid  was  obtained  after  20  minutes.  A  similar  result  was 
obtained  with  NaaSOi,  active  peristalsis,  but  no  secretion 
being  caused  in  an  m/6  solution.  In  an  m/2  solution,  how- 
ever, a  considerable  quantity  of  fluid  collected  in  the  loop. 

A  loop  28  cm.  long  suspended  in  m/8  NaF  exhibited 
active  peristaltic  movements  which  continued  for  less  than 
10  minutes.  At  the  end  of  20  minutes  the  loop  was  found 
to  contain  0.8  c.c.  of  a  clear  but  slightly  blood-stained  fluid. 

Loops  suspended  in  m/6  NaCl  containing  m/6  or  m/8 
BaCls  in  the  proportion  of  50  to  1  or  70  to  1  showed  very 
strong  muscular  contractions  and  a  well  marked  secretion 
of  fluid.  The  muscular  movements  were  characteristic  of 
barium.  Violent  local  contractions  and  firm  constrictions 
of  the  intestine  together  with  strong  peristaltic  movements 
took  place.  The  loops  always  contained  a  distinct  and 
measurable  quantity  of  fluid  after  being  suspended  in  this 
fluid,  as  may  be  seen  in  the  table  which  follows. 

Loops  placed  in  m/6  CaClg  showed  no  muscular  move- 
ments whatever,  nor  did  any  fluid  gather  in  the  lumen. 
This  is  in  marked  contrast  to  the  behavior  of  the  loops  in 
the  solutions  already  described.  In  equal  parts  of  m/6 
NaCl  and  m/6  CaCL  no  movements  or  secretion  took  place. 

The  results  of  a  number  of  these  experiments  may  be 
observed  in  the  following  table : — 


54 


No. 

Salt 

Concentra- 
tion of 
Solution 

Time 

Length 
of  loop 

Muscular 

movements  and 

duration 

Secretion  of 
■fluid 

1 

NaCl 

m/8 

40  min. 

30  em. 

Active  peristalsis 
40  min. 

0.0. 

2 

" 

» 

20     " 

23    " 

Active  peristalsis 
40  min. 

0.0    . 

3 

" 

ni/2 

20     " 

30    " 

Strong     contrac- 
tions 5  min. 

0.8  c.c.  clear  yel- 
low fluid. 

4 

" 

» 

20     " 

30    " 

Strong     contrac- 
tions 5  min. 

0.6  c.c.  clear  yel- 
low fluid. 

5 

Sod.  Cit. 

m/8 

20     " 

20    " 

Active  peristalsis 
20  min. 

0.0 

6 

» 

m/2 

20     " 

32    " 

Violent    contrac- 
tions 2-3  min. 

0.4  c.c.  clear  yel- 
low fluid. 

7 

Na2  SO4 

m/8 

20     " 

33    " 

Active  peristalsis 

0.0 

8 

m/2 

20     " 

30    " 

Strong  contrac- 
tions   of    short 
duration. 

1.5  c.c.  clear  yel- 
low fluid. 

9 

NaF 

m/8 

20     " 

28    " 

Strong   contrac- 
tions 10  min. 

0.8  c.c. 
slightly  bloody. 

10 

/NaCl 
I  BaCl2 

m/8-70  c.c.  "1 
m/8-  1  c.c.  J 

20     » 

25    " 

Active  mov'm'ts. 

0.6  c.c.  clear  yel- 
low fluid. 

11 

I) 

" 

20     " 

46    " 

Active  mov'm'ts. 

0.8  c.c. 

12 

" 

» 

20     " 

60    " 

Active  mov'm'ts. 

1.2  c.c. 

13 

i> 

" 

20     " 

31     " 

Active  mov'm'ts. 

1.2  c.c. 

14 

f  NaCl 
1  BaCl2 

m/8~50  c.c.  I 
m/8-  1  c.c.  J 

1st  20  min. 
2nd  20     " 

63    " 

Active  mov'm'ts. 

1.6  c.c.  I 
0.2  c.c. J 

15 

BaCl2 

m/8-50  c.c.  1 

1st  20  min. 
2nd  20  min. 

32    " 

Violent    contrac- 
tions. 

2.7  c.c.  I 
0.2  c.c. j 

16 

/NaCl 
1  BaCl2 

m/8-30  c.c.  \ 
m/8-30  c.c.  j 

20  min. 

23    " 

Violent    contrac- 
tions. 

0.9  c.c. 

17 

CaCl2 

m/8 

20     " 

20    " 

None 

None 

18 

n 

» 

20     " 

15    " 

i> 

» 

19 

/  CaCl2 
I  NaCl 

m/8-50  c.c.  I 
m/8-50  c.c.  / 

20     " 

10    " 

» 

W 

20 

/  CaCl2 
I  NaCl 

m/2-50  c.c.  \ 
m/2-50  c.c.  j 

20     " 

15    " 

Slight  movements 
not  peristaltic 
in  character. 

n 

21 

/CaClo 
iNaCl 

m/1-50  c.c.  1 
m/1-50  c.c.  j 

20     " 

15    " 

Slight  movements 
not  peristaltic 
in  character. 

Slight  trace. 

22 

(NaCl 
i  BaCl2 
lCaCl2 

m/8-30  c.c.  "1 
m/8-  1  c.c.  > 
m/8-30  c.c. ) 

20     " 

35    " 

Irregular  contrac- 
tions, not  strong 

None. 

23 

fNaCl 

i  BaCl2 

CaCl2 

m/8-30  c.c.  "1 
m/8-  1  c.c.  (- 
m/8-30  c.c.  j 

20     " 

30     " 

Irregular  contrac- 
tions, not  strong 

0.2  c.c. 

24 

/  BaCl2 
1  CaCl2 

m/8-  1  c.c.  I 
m/8-50  c.c.  J 

20     " 

30     " 

Irregular  contrac- 
tions. 

0.2  c.c. 

55 


It  is  interesting  to  note  again  here  that  the  secretion  into 
these  loops  is  almost  uniformly  inhibited  by  the  presence  of 
calcium.  When  barium  is  also  present  in  the  solution  this 
inhibition  is  only  partial.  The  action  of  barium  is  never 
entirely  counteracted  by  calcium  chloride. 

The  experiments  further  show  that  the  saline  purgatives 
act  on  the  intestine  not  only  when  it  has  its  normal  position 
and  connections  with  the  rest  of  the  body,  but  also  when  it 
is  entirely  isolated.  This  eliminates  in  the  first  place  the 
possibility  of  the  solutions  acting  entirely  through  the  cen- 
tral nervous  system.  It  is  possible  that  the  salts  have  some 
influence  on  the  central  nervous  system,  but  from  these  ex- 
periments it  seems  probable  that  their  main  action  is  either 
on  the  glandular  and  muscular  tissues  themselves,  or  on  the 
plexuses  of  Auerbach  and  Meissner  in  the  intestinal  walls. 

As  I  have  already  shown,  the  action  of  a  saline  purga- 
tive on  the  intestine  consists  of  two  parts,  the  increase  of 
the  peristaltic  activity  and  the  increase  of  the  amount  of 
fluid  secreted  into  the  lumen ;  or,  in  other  words,  the  action 
on  the  muscle  and  the  action  on  the  glandular  tissue.  In 
the  experiments  just  described  it  is  clear  that  these  two  sep- 
arate actions  exist  side  by  side.  For  example,  m/8  solutions 
of  sodium  chloride,  citrate,  or  sulphate  cause  well  marked 
peristaltic  movements  or  allow  these  to  continue,  while  no 
secretion  of  fluid  takes  place.  Stronger  solutions  of  these 
salts,  on  the  other  hand,  such  as  m/2  produce  a  distinct 
secretion.  Thus  a  concentration  of  a  salt  which  is  sufficient 
to  produce  muscular  activity  may  not  be  sufficient  to  affect 
the  glandular  tissues.  One  is  tempted  to  conclude  that  in 
the  intestine  it  requires  a  stronger  stimulus  to  produce  se- 
cretory activity  than  it  does  to  cause  muscular  movements. 
It  is  possible  that  this  is  true,  but  the  anatomical  relations 
also  must  be  taken  into  consideration.  The  muscle  coats  lie 
immediately  under  the  thin  peritoneal  layer  through  which 
the  salts  are  absorbed;  and  it  seems  probable  that  in  the 
experiments   described   the   solutions   reached   the   muscle 


56 


more  easily  and  rapidly  than  they  could  the  glandular 
tissue  which  is  situated  on  the  other  side  of  the  muscular 
and  submucous  layers.  Further,  it  must  be  noticed  that 
the  movements  seen  in  m/8  NaCl  may  be  merely  the  con- 
tinuation of  those  caused  by  separation  of  the  loop  f-rom  the 
central  nervous  system. 

The  amount  of  fluid  which  may  be  secreted  by  a  loop  of 
intestine  isolated  from  the  body  is  limited  by  the  absence 
of  the  blood  supply.  The  loop,  as  shown  above,  secretes  a 
certain  amount  of  fluid  in  the  first  10  or  20  minutes.  If  it 
is  then  emptied,  usually  no  more  fluid  appears.  The  quan- 
tity secreted  depends  on  the  amount  of  fluid  contained  in 
the  intestinal  walls  at  the  time  of  its  removal  from  the  body. 
No  fluid  passes  from  the  solution  in  which  the  loop  is  sus- 
pended into  the  lumen  of  the  loop ;  no  current  is  established 
through  the  walls  from  the  outside  inwards.  It  seems  pos- 
sible to  supply  the  stimulus  for  secretion  in  the  solution  in 
which  the  loop  is  suspended;  but  it  is  not  possible  in  this 
way  to  renew  the  fluid  which  the  glands  have  secreted  into 
the  lumen.  This  can  apparently  be  done  only  through  the 
blood  vessels. 


CHAPTER  VII. 

The  Action  on  the  Intestine  of  Solutions  Containing 
Two  Salts. 

As  stated  above,  it  was  shown  by  Claude  Bernard  and 
by  PMger  that  section  of  the  spinal  cord  below  the  phrenic 
nerve,  or  section  of  the  splanchnic  nerves,  causes  a  marked 
increase  in  the  intestinal  movements,  and  also  an  increase 
in  the  amount  of  fluid  secreted  (Moreau).  These  move- 
ments continue  in  loops  isolated  and  removed  from  the  body 
and  placed  in  m/6  NaCl,  LiCl,  NagSO^,  sodium  citrate,  etc., 
for  varying  periods  of  time.  They  continue  far  longer  in 
NaCl  than  in  any  other  solution.  Calcium  chloride  inhibits 
these  movements,  as  is  the  case  also  with  magnesium  chlo- 
ride. It  was  found,^°  however,  in  making  these  experiments 
with  isolated  loops  removed  from  the  body,  that  with  cer- 
tain mixtures  of  NaCl  or  LiCl  with  CaCls  or  MgCL,  move- 
ments began  after  20  or  25  minutes  of  a  character  differing 
entirely  from  the  movements  seen  in  pure  NaCl.  An  idea 
of  this  phenomenon  may  be  gained  from  the  following  de- 
scription of  experiments. 

A  word  may  be  first  said  with  regard  to  the  methods 
used  in  these  experiments.  In  rabbits  anaesthetized  as 
usual,  the  abdomen  was  opened  and  a  loop  30-40  cm.  in' 
length  isolated  by  ligatures.  By  means  of  a  needle  and 
thread  the  bloodvessels  supplying  the  loop  were  carefully 
tied  and  the  loop  rapidly  excised.  It  was  then  cut  into  a 
number  of  pieces,  usually  four,  which  were  transferred  with 

""  MacCallum,  J.  B. :  University  of  California  Publications,  Phys- 
iology, Vol.  II,  1905,  p.  47. 


58 


as  little  handling  as  possible  to  the  beakers  containing  the 
solutions  to  be  tested.  These  beakers  were  kept  in  a  water 
bath  at  39.5°  C.  It  is  desirable  in  these  experiments  to  use 
loops  which  contain  no  faeces,  since  unknown  substances  in 
the  faeces  might  go  into  solution  and  disguise  the  action  of 
the  salt  being  tested.  For  this  reason  the  upper  part  of  the 
small  intestine  was  principally  used  since  in  the  rabbit  it  is 
usually  empty  or  can  be  readily  emptied.  In  each  set  of 
experiments  the  loops  must  all  come  from  the  same  rabbit, 
for  there  exist  considerable  differences  in  irritability  in 
different  animals.  On  account  of  these  differences  it  is 
necessary  to  have  control  experiments  in  the  case  of  each 
rabbit.  Loops  also  which  have  been  unduly  exposed  to  the 
air  cannot  be  used.  It  is  of  great  importance  to  keep  the 
solutions  at  a  constant  body  temperature. 

(a)  LiCl  and  CaCl^-  A  loop  of  intestine  removed  from 
the  body  and  placed  in  an  m/6  LiCl  solution  at  body  tem- 
perature usually  exhibits  only  slight  movements,  which  soon 
cease.  This  seems  to  vary  somewhat  with  different  rabbits. 
In  some  cases  the  loop  shows  no  movements  at  all,  while  in 
other  instances  it  moves  regularly  for  half  a  minute  and 
then  comes  to  rest  in  the  solution.  These  movements  are 
quiet  and  regular  and  resemble  those  described  in  loops 
immersed  in  m/6  NaCl  solution.  When  a  loop  has  ceased 
to  move  it  does  not  become  active  again.  In  exceptional 
cases  these  movements  may  last  5-10  minutes,  but  rarely 
longer.  The  LiCl  solution  seems  less  favorable  for  the  long 
duration  of  the  movements  than  the  NaCl. 

A  loop  similarly  immersed  in  m/6  CaClg  solution  at 
body  temperature  remains  in  the  great  majority  of  cases 
quite  motionless  from  the  first.  In  some  instances  slight 
movements  appear  immediately  after  it  is  placed  in  the 
solution,  but  these  soon  disappear.  After  25-40  minutes  it 
is  not  uncommon  to  see  the  loop  slowly  straighten  out,  and 
at  the  end  of  this  time  the  length  of  the  loop  is  much  less 
than  it  was  at  first.  This  seems  to  be  due  to  a  slow  contrac- 
tion of  the  longitudinal  muscle  layer,  so  slow  that  no  move- 


59 


ment  can  be  observed.  A  difference  is  seen  also  in  the  shape 
of  the  loops  placed  in  LiCl  and  in  CaClg.  The  former  after 
it  comes  to  rest  is  practically  its  original  length  and  is  coiled 
up  in  a  circle ;  the  latter  is  about  half  its  original  length  and 
is  almost  straight. 

A  loop  similar  to  the  above  placed  in  50  c.c.  m/6  LiCl 
-|-  5  c.c.  m/6  CaClg  behaves  in  a  manner  entirely  different 
from  loops  from  the  same  animal  placed  in  either  LiCl  or 
CaCls  alone.  On  being  first  immersed  in  the  mixture  it  ex- 
hibits practically  no  movements.  Even  in  cases  where  the 
control  loop  is  active  at  first  the  corresponding  loop  in  the 
mixture  of  LiCl  and  CaClg  shows  no  movements.  It  re- 
mains perfectly  quiet  for  10-15  minutes.  Then  sharp  con- 
strictions appear  here  and  there  in  the  loop.  These  are  fol- 
lowed a  second  or  two  later  by  violent  contractions  which 
cause  the  loop  to  coil  upon  itself  in  a  most  active  manner. 
These  contractions  somewhat  resemble  those  caused  by 
BaCla  in  the  intact  intestine.  They  follow  one  another  rap- 
idly so  that  the  loop  is  turned  and  twisted  tightly  upon 
itself.  This  extreme  activity  persists  for  30-45  minutes, 
sometimes  for  an  hour,  while  during  all  this  time  the  con- 
trol loops  in  LiCl  and  in  CaClg  are  entirely  motionless. 
These  movements  are  not  at  all  of  the  same  character  as 
those  which  may  appear  at  the  beginning  in  pure  LiCl  solu- 
tion, and  could  not  be  considered  as  these  same  movements 
delayed.  Such  an  experiment  is  outlined  in  the  following 
table : — 


Time. 

Loops 

50  c.e.  m/6  LiCl 

50  c.c. 
m/6  CaCl2 

placed  in 
solutions  at 

50 

c.c.  m/6  LiCl 

+  5  c.c.  m/6 
CaCl2 

10:05 

no 

movements 

no  movements 

no  movements 

10:10 

no 

movements 

no  movements 

no  movements 

10:15 

no 

movements 

no  movements 

no  movements 

10:19 

no 

movements 

violent  movements  begin 

no  movements 

10:25 

no 

movements 

very  active  movements 

no  movements 

10:30 

no 

movements 

very  active  movements 

no  movements 

10:45 

no 

movements 

very  active  movements 

no  movements 

10:50 

no 

movements 

movement  less  active 

no  movements 

11:00 

no 

movements 

movement  very  slight 

no  movements 

11:15 

no 

movements 

movement  almost  stopped 

no  movements 

11:20 

no 

movements 

no  movements 

no  movements 

60 


By  varying  the  proportions  of  LiCl  and  CaClg  the  re- 
sults may  be  somewliat  changed.  The  characteristic  con- 
tractions may  be  obtained  with  as  small  a  quantity  of  CaClg 
as  in  a  mixture  of  50  c.c.  m/6  LiCl -|-  %  c.c.  m/6  CaOlg. 
The  movements,  however,  last  only  5-10  minutes  and  -are 
less  active  than  in  a  mixture  of  50  LiCl  +  5  CaCU.  This 
latter  mixture  seems  to  be  perhaps  the  most  favorable,  al- 
though almost  equally  powerful  contractions  are  obtained 
with  mixtures  containing  as  much  as  10  c.c.  CaCl,  to  50 
c.c.  LiCl.  When  more  CaCla  than  this  is  added  the  move- 
ments usually  appear  later  and  last  a  much  shorter  time. 
With  equal  parts  of  LiCl  and  CaClg  they  cease  in  15  to  20 
minutes,  while  in  a  mixture  of  5  c.c.  LiCl  -|-  50  c.c.  CaCla 
the  movements  appear  late  and  last  only  4  or  5  minutes. 
The  loops  in  mixtures  with  relatively  much  CaCL  come  to 
rest  in  the  shape  characteristic  of  loops  in  pure  CaClg. 
They  become  shortened  and  are  found  to  be  straightened 
out  at  the  end  of  the  experiment.  Where  relatively  much 
LiCl  is  present  the  loops  remain  almost  their  original  length 
and  are  usually  coiled.  This  is  shown  in  the  following 
table : — 


Time 
11:14 

11:14 
11:20 

11:35 

11:40 

11:50 

12:00 

12:05 
12:10 


50  c.c.  LiCl 

Length  of  loop 

10  cm. 
no  movements 
no  movements 

no  movements 

no  movements 

no  movements 

no  movements 

no  movements 
Length  about 
8  cm. 


50  c.c.  LiCl 

+ 
5  c.c.  CaCl2 

Length  of  loop 

10  cm. 
no  movements 
very  active 

movements 
very  active 

movements 
very  active 

movements 
very  active 

movements 
very  active 

movements 
no  movements 
Length  about 

8  cm. 


50  c.c.  CaClo 

+ 

5  c.c.  LiCl 

Length  of  loop 

10  cm. 

no  movements 

no  movements 

movements 

begin 
Movements 

slow 
no  movements 

no  movements 

no  movements 
Length  about 
4  cm. 


50  c.c.  CaCl2 

Length  of  loop 

10  cm. 
no  movements 
no  movements 

no  movements 

no  movements 

no  movements 

no  movements 

no  movements 
Length  about 
4  cm. 


61 


These  muscular  contractions  which  appear  in  mixtures 
of  LiCl  and  CaCla,  and  do  not  appear  in  either  LiCl  or  in 
CaClg  alone,  are  not  the  continuation  of  movements  caused 
by  separating  the  loop  from  the  central  nervous  system. 
These  latter  movements  which  are  sometimes  seen  for  a 
short  time  following  the  immersion  of  the  loop  in  pure 
LiCl  solution  are  inhibited  by  CaCl,.  Further,  the 
movements  which  come  on  later  in  mixtures  of  LiCl 
and  CaCla  are  of  entirely  different  character,  being  con- 
vulsive and  violent  and  many  times  more  powerful  than 
any  movements  seen  in  pure  LiCl.  If  they  were  the  move- 
ments seen  in  pure  LiCl,  only  delayed  by  the  CaCla,  they 
should  be  more  active  in  solutions  containing  the  least 
CaClg.  This  is  not  the  case,  since  in  a  mixture  of  50  c.c. 
LiCl  -f-  V2  c.c.  CaCla  they  are  by  no  means  so  active  as  in 
50  c.c.  LiCl  -f-  5  c.c.  CaCL.  A  further  experiment  shows 
this  still  more  clearly.  A  loop  placed  in  50  c.c.  m/6  LiCl 
was  allowed  to  come  to  rest,  and  was  left  in  the  solution  for 
10  minutes.  No  movements  whatever  were  to  be  seen  at 
this  time.  There  were  then  added  5  c.c.  m/6  CaCla  to  the 
LiCl  solution  containing  the  motionless  loop.  Within  one 
minute  the  loop  became  violently  active  in  the  characteristic 
way  described  above.  This  activity  continued  for  nearly  an 
hour. 

In  attempting  to  explain  this  phenomenon  one  is 
tempted  to  take  Loeb's  suggestion  as  to  the  action  of  cal- 
cium in  Gonionemus,  namely,  that  it  counteracts  the  pois- 
onous effect  of  the  sodium  chloride.  If  the  LiCl  solution 
were  toxic,  however,  it  is  difficult  to  imagine  that  the  loop 
could  be  restored  suddenly  to  activity  as  described  above 
by  the  addition  of  a  small  quantity  of  CaClg,  after  it  had 
lain  in  pure  LiCl  solution  for  10  minutes.  It  is  also  diffi- 
cult to  consider  calcium  as  a  stimulating  agent  in  this  case, 
since,  as  shown  above,  in  all  other  instances  in  the  intestine 
it  has  the  opposite  action.  Also  calcium  chloride  alone  in 
no  concentration  causes  this  phenomenon.     The  action  of 


62 


CaClj  in  this  instance  is  suggestive  of  the  action  of  a  ca- 
talyser,  the  addition  of  which  enormously  hastens  some 
chemical  reaction.  It  is  possible  that  the  muscular  activity 
in  this  case  depends  on  a  chemical  reaction  which  is  brought 
about  neither  by  LiCl  nor  by  CaCL,  but  by  a  combination 
of  these  two  or  perhaps  by  an  intermediate  product. 

"Whatever  may  be  the  explanation  of  these  phenomena, 
the  fact  remains,  and  is  easy  of  demonstration,  that  an 
effect  is  produced  on  isolated  loops  of  intestine  by  a  com- 
bination of  LiCl  and  CaCL  which  is  entirely  different  from 
what  can  be  produced  by  either  LiCl  or  CaCL  alone. 

(6)  NaCl -\-  CaCl^.  The  phenomena  described  above  as 
occurring  when  isolated  loops  of  intestine  are  immersed  in 
mixtures  of  LiCl  and  CaCU  can  be  produced  also  in  mix- 
tures of  NaCl  and  CaCL.  The  behavior  of  loops  placed  in 
pure  CaCL  and  in  pure  NaCl  has  been  described.  In  the 
former  the  loop  remains  motionless;  in  the  latter  regular 
rhythmical  movements  continue  for  40  minutes  or  more. 

When,  however,  a  loop  is  placed  in  50  c.c.  m/6  NaCl  4" 
10  c.c.  m/6  CaCla  there  are  no  movements  whatever  to  be 
seen  at  first.  The  loops  remains  quiet  for  about  10  minutes. 
The  movements  which  are  seen  from  the  beginning  in  the 
control  loop  in  pure  NaCl  solution  have  apparently  been 
inhibited  by  the  CaClg  present  in  the  mixture.  After  10 
minutes,  however,  the  loop  gradually  becomes  very  active, 
and  "^dolent  contractions  appear  which  are  similar  to  those 
described  as  taking  place  in  mixtures  of  LiCl  and  CaClg. 
The  loop  becomes  much  more  active  than  the  control  loop 
in  pure  NaCl.  The  onset  in  the  LiCl  mixture  is  more  sud- 
den, but  otherwise  the  phenomenon  is  practically  the  same. 
The  movements  in  NaCl  +  CaCL  persist  for  30  or  40  min- 
utes, sometimes  for  an  hour.  When  the  concentration  of 
the  CaCL  in  the  mixture  is  relatively  great  this  effect  is  not 
obtained.    This  is  shown  in  the  following  table : — 


63 


Ol      t^      CO 


o     2 


oiairfi.rfi.o3 


B  H  m  CO  CO  CB  k-' 

°  °  a  t^  t;;  L:  «= 

S  S  o 

o  S  S-  P  P  ?=  ^ 


Sr.    ET.    E^-    b     b 


<      2 


?;     X     X     K 


CD      G>      a>      o 


3    3 


<J  CO  CO  y 

o  t^  M^  o 

^3  (K!  OTQ 

^  cr  Cr  B 


ffl        O.      ®        CB^ 


5    +c 


w         w         S         P 
fB        tB        02        CO 


3     2 


X       X 


Ci      ~     ~ 


£5"  JT  2"  ^  CTQ  OQ 

C6  CD  CD  ^  S  2! 

3  5  3  p  "^ 

£-  £L  2-  S-  3  g 


o9 


3333333333 


CD   CD   ®   CD   CD   O   Q 

3  3  3  3  3  3  3 

CD   CD   CD   CD   CD   CD   CD 


3  3  3 


m    05    00    CO 


29 


3  3  3  3  3  3 


3  3  3 


+ 


O^CDCDCDCDCDCD 

33333333 

CDCDCDCDCDCDCDCD 


OS 


3  3  3  3 


3  3  3  3  3 


CD   O   CD   CD   CD   CD   CD 


3  3  3 


CO    CQ    CO    CQ 


CD   CD   CD   CD   CD   CD     i:d 
C   C   B   d   P   B    to 


64 


Thus  here  also,  as  in  the  case  of  LiCl  and  CaCL,  there 
are  produced  effects  in  mixtures  of  NaCl  and  CaClg  which 
cannot  be  brought  about  by  either  salt  alone.  The  presence 
of  CaClo  seems  to  inhibit  the  movements  which  are  first 
present  in  a  loop  placed  in  NaCl  solution.  When  add^d  in 
small  quantities,  e.g.,  not  more  than  10  c.c.  m/6  CaCla  to 
50  c.c.  m/6  NaCl,  it  produces  after  an  interval  of  10-15 
minutes  very  violent  movements  such  as  are  never  seen  in 
pure  NaCl  solution  nor  in  pure  CaClg.  When,  however,  it 
is  added  in  greater  proportion  than  this,  e.g.,  20  or  more 
c.c.  CaClg  to  50  c.c.  NaCl,  all  movements  are  stopped.  The 
explanation  of  this  is  no  more  clear  than  the  similar  occur- 
rence in  mixtures  of  LiCl  and  CaClg. 

If  a  loop  be  placed  in  a  mixture  of  LiCl  and  NaCl  in 
equal  parts,  movements  appear  such  as  are  seen  in  pure 
NaCl,  but  do  not  persist  for  so  long  a  time.  In  the  mixture 
of  these  two  salts  no  such  result  is  obtained  as  has  been  de- 
scribed in  mixtures  of  LiCl  and  CaClj  or  of  NaCl  and 
CaClo.  Mixtures  of  CaClg  and  MgClg  also  produce  no  such 
movements.  In  these  few  salts  it  seems  to  be  a  mixture  of 
chlorides  of  a  monovalent  with  a  bivalent  metal  which  pro- 
duces the  extreme  activity  of  the  loop,  while  mixtures  of 
chlorides  of  two  monovalent  metals  or  of  two  bivalent  met- 
als do  not  bring  this  about. 


CHAPTER  VIII. 

The  Effect  on  the  Intestine  of  Intravenous 
Saline  Infusions. 

It  has  been  frequently  observed  that  a  quantity  of  fluid 
enters  the  intestine  during  the  intravenous  injection  of 
normal  salt  solution.  According  to  Dastre  and  Loye,"^  the 
fluid  injected  into  the  veins  is  largely  eliminated  by  the 
kidneys,  although  these  organs  may  be  assisted  in  this  func- 
tion by  the  salivary  glands  and  intestine.  These  authors 
have  found  fluid  to  be  present  in  the  intestine  of  rabbits  as 
well  as  in  the  pleural  and  peritoneal  cavities  after  the  in- 
jection of  large  quantities  of  salt  solution.  They  state  that 
in  such  an  intravenous  injection  diarrhea  often  results 
which  may  be  so  pronounced  that  a  clear  fluid  emerges 
from  the  rectum.  KnolP-  also  mentions  the  production  of 
diarrhoea  by  the  injection  of  large  ciuantities  of  NaCl  so- 
lution. 

Magnus^^  in  his  work  on  the  production  of  oedema  of 
the  skin  by  intravenous  infusions  of  salt  solutions  shows  in 
his  tables  that  a  certain  amount  of  fluid  is  eliminated  by 
the  intestines  after  the  kidneys  have  been  removed.  A  rab- 
bit with  both  kidneys  removed  was  infused  with  1,500  c.c. 
normal  salt  solution ;  200  g.  were  eliminated  by  the  intes- 
tine. In  a  second  rabbit  1,010  c.c.  of  fluid  were  injected 
into  the  veins  and  60  g.  were  eliminated  by  the  intestine. 

"^Arch.  de  physiol.  norm,  et  path.,  4  e  serie,  2,  1888,  p.  93;  5  e 
serie,  1,  1889,  p.  253. 

""^  Arch,  fiir  exp.  Path.  u.  Pharm.,  Bd.  XXXVI,  S.  293,  1895. 
^  Arch,  fiir  exp.  Path.  u.  Pharm.,  Bd.  XLII,  S.  250,  1899. 


66 


In  a  dog  1,760  c.c.  were  injected  and  160  g.  eliminated  by 
the  intestine. 

I  have  made  a  number  of  experiments''*  in  which  the 
amount  of  fluid  passing  into  the  intestine  during  the.  in- 
travenous injection  of  large  quantities  of  NaCl  solution  was 
determined  not  only  when  the  kidneys  were  removed  from 
the  circulation,  but  also  when  they  were  active.  As  shown 
by  the  following  experiments,  the  fluid  secreted  by  the  in- 
testine increases  rapidly  when  m/8  or  m/6  NaCl  solution 
is  injected  into  the  blood.  Without  such  an  injection  or 
other  stimulus  very  little  intestinal  juice  can  be  gathered 
in  a  time  as  short  as  that  occupied  by  the  experiments.  In 
a  rabbit's  small  intestine  there  is  usually  found  between  5 
and  10  c.c.  fluid,  often  much  less. 

Exp.  1.  Rabbit.  The  bloodvessels  to  the  kidneys  were 
tied  off  and  two  cannulae  were  put  into  the  intestine,  one 
35  cm.  from  the  pylorus  and  the  other  in  the  lower  part  of 
the  ileum.  Each  loop  was  isolated  by  ligatures.  The  upper 
one  was  about  30  cm.  long  and  the  lower  one  42  cm.  The 
upper  loop  in  the  beginning  contained  5  c.c.  fluid,  which 
were  removed.  The  lower  loop  was  empty.  During  the 
first  hour  100  c.c.  m/8  NaCl  were  forced  into  the  blood  and 
5.2  c.c.  fluid  appeared  in  the  upper  loop  and  nothing  in  the 
lower  loop.  During  the  second  hour  240  c.c.  NaCl  solution 
were  injected  and  5.4  c.c.  fluid  appeared  in  the  upper  loop 
and  13.6  c.c.  in  the  lower  loop.  During  the  third  hour  160 
c.c.  NaCl  solution  were  introduced;  6.6  c.c.  fluid  appeared 
in  the  upper  loop  and  15.5  c.c.  in  the  lower.  The  infusion 
was  then  stopped  and  26  c.c.  were  found  in  the  part  of  the 
small  intestine  not  included  in  the  loops.  The  total  amount 
thus  secreted  by  the  intestine  in  three  hours  was  72.3  c.c. 
This  is  14.46%  of  the  quantity  injected. 

Exp.  2.  In  another  rabbit  with  kidneys  removed,  470 
c.c.  NaCl  solution  were  injected  during  three  hours,  and  78 

*^  MacCallum,  J.  B. :  University  of  California  Publications,  Phys- 
iology, Vol.  I,  1904,  p.  125. 


67 


c.c.  fluid  obtained  from  the  intestine,  which  is  about  16.6% 
of  the  quantity  injected. 

Exp.  3.  In  a  rabbit  in  which  the  kidneys  were  left  in- 
tact, 547  c.c.  m/6  NaCl  solution  were  injected  into  the  blood. 
49.5  c.c.  were  secreted  in  3  hours  and  30  minutes  by  the 
intestine.  This  is  about  9%  of  the  total  quantity  of  fluid. 
The  quantity  of  fluid  secreted  into  the  loop  in  the  first  half 
hour  was  1.8  c.c. ;  in  the  third  half  hour,  2.9  c.c. ;  in  the  fifth 
half  hour,  6.6  c.c. 

Exp.  4.  In  a  second  rabbit  in  which  the  kidneys  were 
untouched,  the  quantity  of  m/8  NaCl  solution  introduced 
was  390  c.c. ;  about  40  c.c.  of  fluid  were  obtained  during 
three  hours  from  the  intestine.  This  is  10.25%  of  the 
amount  injected.  In  the  first  hour  5  c.c.  were  secreted  into 
the  loop ;  in  the  second  hour  7  c.c. ;  and  in  the  third  hour 
11.1  c.c.  In  the  rest  of  the  small  intestine  17  c.c.  were 
found. 

It  is  clear  from  these  experiments  that  a  considerable 
proportion  of  the  fluid  injected  in  this  way  is  eliminated  by 
the  intestine.  The  quantity  is  somewhat  greater  if  the  kid- 
neys are  extirpated.  There  is,  however,  a  limit  to  the 
amount  that  can  be  excreted  by  the  intestine,  and  never, 
as  in  the  case  of  the  kidney,  does  the  amount  excreted  ap- 
proximate the  amount  injected.  The  action  of  such  infu- 
sions on  the  intestine  is  nevertheless  quite  similar  to  that 
on  the  kidneys,  and  in  many  other  ways  the  intestine  may 
be  regarded  as  an  excretory  organ  which  can  to  some  extent 
take  on  the  functions  of  the  kidney.  The  intestinal  juice 
contains  many  substances  contained  by  the  urine.  Among 
the  more  conspicuous  of  these  is  urea,  which  was  shown  by 
Claude  Bernard*^^  to  be  excreted  into  the  intestine  as  well 
as  the  stomach.  He  found  that  it  is  readily  broken  up  .in 
the  intestinal  juice,  so  that  in  many  cases  only  salts  of  am- 
monia remain. 


*"  Lemons  sur  les  proprietes  physiologiques  et  les  alterations  patho- 
logiques  des  liquides  de  1 'organisme,  II  Tome,  Paris,  1859.  Deuxieme 
Le§on. 


68 


Pj.ggpe  demonstrated  the  presence  of  urea  in  the  intes- 
tinal juice  of  the  sheep.  He  found  its  concentration  there 
to  be  0.248%.  In  the  intestinal  juice  of  rabbits  P'^  have 
found  that  small  quantities  of  urea  exist  both  before  and 
after  extirpation  of  the  kidneys.  It  is  present  not  only  in 
the  normal  intestinal  juice,  but  also  in  the  fluid  obtained 
from  the  intestine  after  the  infusion  of  large  quantities  of 
m/6  NaCl.  Weintrand*'^  has  demonstrated  uric  acid  in  the 
intestinal  juice. 

Secretion  of  sugar  into  the  intestine.  Another  instance 
of  the  way  in  which  the  intestine  can  to  some  extent  take 
up  the  function  of  the  kidney  is  shown  by  the  secretion  of 
sugar  by  the  gut  following  the  injection  of  large  quantities 
of  normal  salt  solution.  It  was  shown  by  Bock  and  Hoff- 
mann'"' that  the  injection  of  1%  NaCl  solution  into  the 
circulation  of  a  rabbit  caused  transient  glycosuria.  Large 
quantities  of  the  solution  were  injected  at  the  rate  of  25-30 
c.c.  each  5  minutes,  and  the  glycosuria  appeared  in  from  20 
minutes  to  1  hour  and  30  minutes  after  the  beginning  of 
the  infusion.  After  a  number  of  hours  (6-7)  the  glyco- 
suria diminished  in  their  experiments  and  finally  disap- 
peared, although  the  infusion  of  salt  and  the  flow  of  urine 
continued.  They  found  that  the  entire  quantity  of  sugar 
eliminated  was  in  one  case  1.632  g.,  and  in  another  case 
2.04  g.  The  percentage  of  sugar  in  the  urine  reached  0.136 
and  0.219  respectively  in  the  two  experiments.  These  facts 
were  confirmed  by  Kiilz,''°  who  found  also  that  section  of 
the  splanchnics  prevented  the  glycosuria.  The  experiments 
lately  published  by  M.  H.  Fischer''^  show  that  the  glyco- 
suria is  caused  not  only  by  NaCl,  but  by  certain  of  the  salts 

""  Archiv  fiir  die  gesanunte  Physiologie,  Bd.  61,  1895,  p.  378. 

'''' Loc.  cit. 

*=«  Chemische  Centralblatt,  Leipzig,  Bd.  II,  1895,  S.  310. 

^^  Bock  and  Hoffmann  :  Arch,  fiir  Anat.,  Physiol,  und  wissen- 
schaftl.  Med.  (Eeichert  und  DuBois-Eeymond),  p.  550,  1871. 

'"KiJLZ:  C.  Eckhard's  Beitrage,  Bd.  6,  S.  117,  1872.  (Quoted  by 
Pfliiger,  Arch,  fiir  die  gesammte  Physiologie,  Bd.  96,  1903,  S.  313.) 

'^M.  H.  Fischer:  University  of  California  Publications,  Physiol- 
ogy, Vol.  I,  pp.  77  and  87,  1904. 


69 


which  were  shown  by  Loeb'^'-  to  produce  muscular  twitch- 
ings.  He  further  showed  that  calcium  has  the  power  of 
suppressing  the  glycosuria. 

This  secretion  of  sugar  by  the  kidneys  following  intra- 
venous infusions,  together  with  the  facts  shown  above  that 
fluid  is  eliminated  to  some  extent  by  the  intestine  in  the 
absence  of  the  kidneys,  led  me  to  inquire  whether  the  in- 
testine also  secretes  sugar  when  the  kidneys  have  been  ex- 
tirpated and  a  large  amount  of  NaCl  solution  is  injected. 
A  number  of  experiments  were  made  to  determine  this.  I 
have  found'^^  in  brief  that  with  the  infusion  of  large  quan- 
tities of  m/6  NaCl  solution  into  the  circulation  sugar  is 
abundantly  secreted  into  the  intestine.  This  takes  place 
not  only  when  the  kidneys  are  removed,  but  also  when  they 
are  intact,  and  are  also  eliminating  sugar.  This  may  be  seen 
in  the  following  tables : — 

Rabbit — Blood  vessels  of  kidney  ligatured;  cannula  in 
upper  part  of  small  intestine,  with  loop  35  cm.  tied  off. 
Loop  emptied;  contents  5  c.c,  which  contained  no  sugar. 


Time 

NaCl  m/6 
injected 

Intestinal 
juice 

Sugar  examination  of 
intestinal  juice 

10:00 

Infusion  begun 

Loop  emptied, 
5  c.c. 

No  sugar 

10:30 

20  c.c. 

3  c.c. 

No  sugar 

11:00 

40  c.c. 

3  c.c. 

No  sugar 

11:30 

20  c.c. 

4  c.c. 

No  sugar 

12:00 

120  c.c. 

6  c.c. 

Trace  of  sugar 

12:30 

200  c.c. 

12  C.C. 

Sugar  abundant 

1:00 

—  c.c. 

28  C.c. 

Sugar  abundant 

400  c.c. 


Here  the  sugar  appeared  in  the  intestinal  juice  after 
about  200  c.c.  NaCl  solution  had  been  injected.  The  injec- 
tion was  made  in  each  case  into  the  vein  of  the  ear  by  means 


"LOEB,  J:  Festschrift  fiir  Tick,  1899;  Pfliiger's  Archiv,  1902, 
XCI,  p.  248. 

'^  MacCallum,  J.  B. :  University  of  California  Publications,  Phys- 
iology, Vol.  I,  1904,  p.  125. 


70 


of  a  pressure  bottle  connected  with  the  water  tap.  The 
pressure  bottle  was  in  turn  connected  with  a  bottle  holding 
the  solution,  which  was  thus  forced  out  at  a  constant  rate 
through  a  long  rubber  tube  immersed  in  water  at  40°  C. 
A  hypodermic  needle  was  fastened  in  the  end  of  this  tube 
and  inserted  into  the  marginal  vein  of  the  rabbit's  ear.  In 
this  way  the  quantity  of  fluid  injected  could  be  accurately 
measured  and  controlled.  The  salt  solution  after  passing 
through  the  long  tube  reached  the  ear  at  approximately 
body  temperature.  It  is  of  the  greatest  importance  to  pro- 
tect the  intestinal  loops  in  every  way  possible  from  loss  of 
heat  or  from  drying. 

In  the  above  experiment  the  intestinal  glycosuria,  if 
such  a  term  may  be  applied  to  this  phenomenon,  appears 
under  circumstances  which  are  exactly  the  same  as  those 
necessary  for  the  production  of  sugar  in  the  urine  by  saline 
infusions.  A  further  example  of  this  is  shown  in  the  fol- 
lowing experiment : — 

Rabbit — Blood  vessels  of  both  kidneys  ligatured.  Intes- 
tinal loop  including  duodenum  32  cm.  long.  In  the  loop 
were  found  3  c.e.  fluid  which  contained  no  sugar. 


Time 
9:45 

NaCl  in/6 
injected 

Infusion  begun 

Intestinal 
jniee 

Loop  emptied, 

3     c.e. 

Sugar  examination  of 
intestinal  juice 

No  sugar 

10:15 

10  c.e. 

3     c.e. 

No  sugar 

10:45 

70  c.e. 

3     e.c. 

No  sugar 

11:15 

75  c.e. 

3.2  e.c. 

No  sugar 

11:45 
12:15 

85  c.e. 
80  e.c. 

5     c.e. 

9.5  c.e. 

Sugar  abundant  |  0*222% 
Sugar  abundant  0.25% 

12:45 

150  e.c. 

21     e.c. 

Sugar  abundant 

470  c.e. 

Here  the  sugar  appeared  after  the  infusion  of  about 

240  c.e.  NaCl  solution.    The  experiment  was  not  carried  on 

to  see  how  long  the  sugar  would  continue  to  be  present  in 

the  intestinal  juice.     The  animal  was  killed,  and  it  was 


71 


found  that  the  remaining  loops  of  the  small  intestine  held 
32  c.c.  of  fluid  which  contained  sugar.  The  stomach  con- 
tents included  about  40  c.c.  fluid  which  also  contained 
sugar.  Of  the  470  c.c.  of  fluid  injected,  78.7  c.c.  were  elimi- 
nated by  the  small  intestine  and  40  by  the  stomach.  The 
alimentary  canal,  then,  exclusive  of  the  large  intestine,  elim- 
inated about  118  c.c.  of  the  fluid  introduced,  which  is  ap- 
proximately 25%. 

Quantitative  estimations  of  the  sugar  in  the  intestinal 
juice  in  this  case  were  made.  The  amount  varied  between 
0.2  and  0.3%.  I  have  not  attempted  to  ascertain  the  total 
quantity  of  sugar  which  may  be  obtained  from  the  intestinal 
juice  by  continued  infusion  of  salt  solution.  In  the  case  of 
the  urine.  Bock  and  Hoffmann  made  such  determinations 
and  found  that  the  kidney  eliminated  in  one  case  1.632  g. 
and  in  another  case  2.04  g.  sugar.  M-  H.  Fischer  found  that 
the  concentration  of  sugar  in  the  urine  of  a  rabbit  rarely 
exceeds  0.25%  after  infusion  of  m/6  NaCl. 

Thus  the  intestine  eliminates  sugar  in  a  way  that  en- 
tirely resembles  its  elimination  by  the  kidneys.  The  sugar 
appears  in  the  blood  after  the  infusion  of  a  certain  amount 
of  the  salt  solution  and  is  excreted  by  the  kidney.  If  the 
kidneys  are  removed,  it  is  excreted  by  the  intestine.  But 
even  when  the  kidneys  are  intact  there  is  a  certain  amount 
of  sugar  excreted  by  the  intestine,  just  as  a  part  of  the  fluid 
injected  is  eliminated  by  the  intestine  when  the  kidneys  are 
still  active.  As  shown  in  the  following  experiment,  the  sugar 
appears  both  in  the  intestinal  juice  and  in  the  urine.  The 
quantity  of  sugar,  however,  is  greater  in  the  urine  than  in 
the  intestinal  juice.  In  the  urine  it  was  found  to  be  about 
0.2%,  in  the  intestinal  juice  considerably  less.  The  quan- 
tity of  urine  also  is  greater  than  the  quantity  of  intestinal 
juice.  Therefore  the  greater  proportion  of  the  sugar  is 
excreted  by  the  kidneys. 


72 


Rabbit — Cannula  placed  in  bladder.  Kidneys  intact. 
Cannula  in  loop  of  upper  part  of  small  intestine  35  cm. 
long.    Loop  contained  4.2  c.c.  fluid ;  no  sugar. 


Time. 

NaClf 
injected. 

Intestinal  juice. 

Urine. 

Quantity. 

Sugar  examination 

Quantity. 

Sugar  examination. 

9:45 

Infusion 
begun. 

Loop  emp'd, 
4.2  c.c. 

No  sugar. 

Bladder 
emptied,  5  c.c. 

No  sugar. 

10:15 

5  c.c. 

1.8  c.c. 

"        " 

0.0 

10:45 

50   " 

2.2    " 

»        " 

0.0 

11:15 

80   " 

2.9    " 

i>        I) 

4.0  e.c. 

No  sugar. 

11:45 

92  " 

3.8    " 

I!             » 

15.0 

Sugar  present. 

12:15 

120   " 

6.6    " 

Sugar  present. 

38.0 

Much  sugar. 

12:45 

150   " 

7.8    " 

n                  n 

40.0 

"         " 

It  is  interesting  to  note  in  connection  with  these  experi- 
ments the  secretion  of  sugar  into  the  stomach  which  fol- 
lowed the  intravenous  infusion  of  NaCl  solution.  Ordi- 
narily in  the  normal  rabbit  only  a  very  small  quantity  of 
fluid  can  be  obtained  from  the  stomach.  This  was  not  found 
in  my  experiments  to  contain  sugar.  In  one  case  after  the 
infusion  of  470  c.c.  NaCl  solution  the  stomach  contained 
about  40  c.c.  of  fluid.  In  a  second  instance  32.8  c.c.  of  fluid 
were  secreted  by  the  stomach  during  2  hours  and  30  min- 
utes, during  which  time  390  c.c.  NaCl  solution  were  injected. 
In  both  these  experiments  sugar,  which  was  not  present  in 
the  beginning,  appeared  in  considerable  quantities  after  the 
infusion  had  continued  for  a  little  time.  Thus  the  stomach 
excretes  sugar  under  circumstances  similar  to  those  under 
which  it  is  excreted  by  the  intestine.  Claude  Bernard^* 
describes  the  presence  of  sugar  in  the  gastric  contents  of 
diabetic  patients.  He  quotes  McGregor  as  having  made  the 
observation  by  causing  patients  to  vomit.  On  examination 
of  the  gastric  contents  sugar  was  demonstrated.  It  seems 
possible  that  in  this  case  the  food  might  have  contained  a 
reducing  substance. 


''*  Leqons  sur  les  proprietes  physiologiques  des  liquides  de  1  'orga- 
nisme,  T.  II,  1859,  p.  74. 


73 


Thus  a  study  of  the  effect  of  saline  infusions  on  the  in- 
testine leads  us  to  the  idea  of  the  alimentary  canal  as  in 
some  sense  a  subsidiary  excretory  organ.  In  addition  to  its 
other  better  known  functions,  the  intestine  can  to  some  ex- 
tent take  on  some  of  the  functions  of  the  kidney.  As  shown 
above,  it  not  only  tends  to  eliminate  an  excess  of  fluid  forced 
into  the  circulation,  but  also  excretes  urea  and  uric  acid. 
Further,  under  circumstances  which  cause  glycosuria,  sugar 
is  also  excreted  by  the  intestine. 


CHAPTER  IX. 

Mode  of  Action  of  the  Saline  Cathartics. 

Since  the  discovery  of  sodium  sulphate  by  Glauber  in 
the  middle  of  the  seventeenth  century,  and  the  preparation 
of  the  double  tartrate  of  sodium  and  potassium  at  Rochelle 
some  fifteen  years  later,  the  saline  cathartics  have  been  in 
constant  use  among  physicians.  Attempts  have  been  made 
also  from  the  first  to  explain  in  some  way  their  mode  of 
action;  but  it  was  not  until  the  discovery  of  the  osmotic 
property  of  salts  that  any  explanation  which  seemed  satis- 
factory was  made.  Poiseuille'^^  and  Liebig'^®  both  advanced 
the  theory  that  the  purgative  action  of  salts  was  due  to  their 
power  of  attracting  water  into  the  lumen  of  the  intestine, 
i.e.,  to  their  power  of  endosmosis.  This  seemed  at  first  sight 
to  be  very  satisfactory  and  to  account  well  for  the  increased 
amount  of  fluid  in  the  faeces  following  the  administration 
of  a  saline  cathartic.  The  theory  did  not,  however,  take 
into  consideration  other  substances  whose  osmotic  power  is 
as  great  as  that  of  the  purgative  salts,  but  which  have  no 
purgative  action  whatever.  It  was  later,  however,  supported 
by  Rabuteau'^'^  in  an  experiment  in  which  he  claimed  to  have 
found  that  the  intravenous  injection  of  a  large  quantity  of 
sodium  sulphate  produced  constipation,  while  the  same  salt 
given  by  mouth  causes  purgation.  This  he  ascribed  to  the 
flow  of  fluid  towards  the  salt  in  each  case  due  to  its  osmotic 


^'  Eeeherch.  experiment,  sur  les  mouvements  des  liquides  dans  les 
tubes  de  petits  diametres,  Paris,  1828.    Quoted  from  Hay. 
■^^  Tiber  die  Saftbewegung,  1848. 
"L 'Union  medicale,  1871,  50,  51.    Gaz  med.  de  Paris,  1879. 


75 


pressure.  This  experiment  lacks  confirmation,  and  indeed 
it  has  been  shown  above  that  sodium  sulphate  and  other 
saline  cathartics  produce  increased  peristalsis  and  in  some 
cases  increase  of  fluid  in  the  intestine  when  introduced  in- 
travenously or  applied  on  the  serous  surfaces  of  the  intes- 
tine. And  these  evidences  of  a  purgative  action  appear 
much  more  rapidly  and  with  smaller  doses  than  when  the 
salt  is  placed  in  the  lumen  of  the  intestine.  Claude  Ber- 
nard^^  states  in  his  criticism  of  this  theory  that  the  intra- 
venous injection  of  sodium  sulphate  causes  purgation,  and 
further  draws  attention  to  the  fact  that  on  this  theory  of 
the  endosmotic  action  of  cathartics,  sugar,  which  has  a  high 
osmotic  power,  should  be  among  the  more  powerful  purga- 
tives. It  was  further  shown  by  other  investigators  that  of 
several  purgative  salts,  the  most  powerful  was  not  the  one 
with  the  highest  osmotic  power. 

Headland,''^  believing  that  all  medicines  must  first  pass 
into  the  circulation  before  they  act,  claimed  that  the  saline 
purgatives  are  absorbed  from  the  intestine  and  are  again 
excreted  lower  down  in  the  intestine,  and  in  being  excreted 
they  stimulate  the  glands  to  secrete. 

A  little  later  than  this  it  was  shown  by  Moreau^''  and 
others  that  solutions  of  purgative  salts  placed  in  loops  of 
intestine  which  had  been  tied  off  caused  an  increased  secre- 
tion of  fluid  into  the  intestine.  Brieger^^  further  confirmed 
this  with  better  methods  and  showed  that  the  fluid  was  a 
real  secretion,  and  not  an  inflammatory  exudate,  or  a  trans- 
udation. 

Thiry  in  a  series  of  experiments  was  unable  to  produce 
increased  secretion  of  fluid  from  a  Thiry -Vella  fistula  by. 
the  introduction  of  sulphate  of  magnesia.     He  therefore 
concludes  that  the  action  of  saline  cathartics  is  due  solely 


^'  Substances  toxiques  et  medicamenteuses,  1857. 
"  Action  of  Medicines,  1867. 

^°  Archiv.  general  d.  medicine,  VI  Serie  f .  XVI,  1870.     Centralbl. 
d.  medicin.  Wiss.,  1868,  p.  209. 
«i  Arch,  f .  exp.  Path.  u.  Pharm.,  Bd.  VIII,  1878,  S.  355. 


76 


to  an  increase  in  peristaltic  activity.  Eadziejewski^-  held  a 
similar  theory  and  made  many  experiments  in  an  attempt  to 
prove  that  an  increase  in  peristaltic  activity  was  the  main 
result  of  the  administration  of  a  saline  purgative.  In  con- 
nection with  this  it  may  be  noted  that  van  Braam-Hoiick- 
geest^^  concluded  from  his  experiments  that  saline  purga- 
tives do  not  increase  the  peristaltic  activity  of  the  intestine. 
It  is  difficult  to  imagine  how  these  results  could  be  obtained. 

Hay^*  quotes  Aubert,  Buchheim,  and  Wagner  as  holding 
the  theory  that  in  addition  to  causing  an  increased  peri- 
stalsis, the  salt  is  slowly  absorbed,  and  tends  to  prevent  the 
absorption  of  fluid  from  the  intestine.  This  theory  was  held 
also  by  Schmiedeberg,®^  who  claimed  that  the  purgative 
salts  were  absorbed  with  difficulty  and  reached  the  lower 
parts  of  the  intestine  unchanged.  In  the  large  intestine 
the  salts,  according  to  this  hypothesis,  prevent  the  faeces 
from  becoming  compact  by  inhibiting  the  absorption  of 
water  from  the  lumen.  This  explanation  of  the  action  of 
cathartic  salts  has  been  widely  accepted  and  has  been  sup- 
ported by  Wallace  and  Cushny,^*^  who  claim  in  addition  that 
the  salts  of  acids  which  form  insoluble  compounds  with 
calcium  are  especially  active  in  inhibiting  the  absorption  of 
fluids  from  the  intestine. 

Loeb  in  studying  the  action  of  salts  in  the  production  of 
muscular  twitchings  in  voluntary  muscles,  and  of  hyper- 
sensitiveness  of  the  skin  and  nervous  elements,  recognized 
the  fact  that  the  salts  which  had  these  actions  included  those 
commonly  known  as  saline  purgatives.  He  says  in  this  con- 
nection :  "I  will  not  deny  the  effect  of  these  salts  upon  the 
phenomena  of  absorption  of  water  from  the  intestine,  but  it 
is  obvious  from  our  experiments  that  the  same  salts  must 
increase  the  irritability  of  the  nerves  and  muscles  of  the 

8=  Eeichert 's  u.  DuBois-Eeymond 's  Arehiv,  1870,  S.  37. 

^'Pfliiger's  Arehiv,  1872,  S.  266. 

^  Loc.  cit. 

*^  Arzneimittellehre,  Leipzig,  1883. 

«'  Amer.  Journ.  Physiol.,  1898,  Vol.  I,  p.  411. 


77 


intestine,  and  that  this  must  facilitate  the  production  of 
peristaltic  motions,  possibly  through  the  mechanical  or  con- 
tact stimuli  of  the  faeces  upon  the  nerve  endings  or  the 
muscular  wall  of  the  intestine. '  '^' 

My  own  experiments  which  I  have  described  above  sup- 
port this  suggestion  of  Loeb's.  In  the  first  place  it  was 
found  that  the  subcutaneous  or  intravenous  injection  of  one 
of  these  salts,  especially  sodium  citrate,  caused  muscular 
twitchings  in  the  living  rabbit.  This  had  already  been  done 
by  Loeb  in  the  frog.  In  both  cases  the  injection  of  calcium 
chloride  inhibits  the  twitchings.  As  shown  above,  there 
are  produced  in  a  rabbit  by  such  an  injection  of  a  purg- 
ative salt  not  only  muscular  twitchings,  but  also  increased 
peristaltic  movements,  and  an  increased  flow  of  fluid  into 
the  intestine.  The  subsequent  injection  of  calcium  chlo- 
ride was  shown  to  inhibit  both  the  increased  secretion  and 
the  increased  movements  of  the  intestine.  There  thus  seems 
to  be  a  very  distinct  analogy  between  the  action  of  these 
salts  in  producing  twitchings  in  voluntary  muscles  and  the 
production  of  their  purgative  effect ;  and  a  similar  analogy 
between  the  suppression  of  the  former  and  the  suppression 
of  the  latter  by  calcium  chloride.  One  is  tempted  to  sup- 
pose that  these  purgative  salts  act  by  removing  calcium 
from  the  tissues,  as  suggested  by  Loeb,  in  the  production  of 
muscular  twitchings,  since  they  are  all  calcium  precipitants. 
There  is,  however,  no  direct  proof  of  this,  and  other  saline 
purgatives  such  as  BaCla  and  Hg^Oh  certainly  have  an 
action  which  is  independent  of  calcium. 

There  thus  seems  to  be  produced  by  saline  purgatives  a 
condition  of  increased  irritability  in  the  intestine  analogous 
to  the  increased  irritability  produced  in  the  voluntary 
muscles.  As  a  result  of  this  the  two  main  activities  of  the 
intestine  are  increased,  namely,  the  peristaltic  activity  and 
the  secretory  activity.     The  action  of  the  saline  purgative, 

"  Loeb  :  Decennial  Publications,  University  of  Chicago,  Vol.  X, 
1902,  p.  10. 


78 


then,  as  far  as  v/e  know,  consists  of  two  main-  parts.  The 
peristaltic  movements  are  greatly  increased  in  rapidity  and 
force,  and  the  faeces  are  carried  rapidly  from  the  upper  to 
the  lower  parts  of  the  intestine.  They  are  thus  passed 
through  the  large  intestine  in  so  short  a  time  that  the  fluid 
they  already  contain  has  not  time  in  which  to  be  reabsorbed, 
a  process  which  apparently  takes  place  normally  in  the 
large  intestine.  At  the  same  time  there  is  a  much  larger 
quantity  of  fluid  secreted  into  the  lumen  of  the  intestine 
than  takes  place  in  the  normal  animal.  The  faeces  which 
are  thus  forced  rapidly  through  the  gut  by  the  increased 
peristaltic  movements  are  more  fluid  than  normal.  This  to- 
gether with  the  rapid  passage  of  the  faeces  accounts  for 
their  fluid  character  when  a  saline  purgative  is  given. 

"Whether  or  not  the  saline  purgatives  also  inhibit  the 
absorption  of  fluid  from  the  intestine  cannot  be  stated  with 
certainty.  The  experiments  of  Wallace  and  Cushny  leave 
out  of  account  the  increased  secretion  of  fluid  into  the  in- 
testine caused  by  the  purgative,  a  process  which  undoubt- 
edly takes  place.  Thus  in  comparing  the  amount  of  NaCl, 
and  the  amount  of  a  saline  purgative  absorbed  in  a  given 
time  from  separate  loops  under  the  same  conditions,  it  is 
not  surprising  that  the  amount  of  NaCl  solution  found  in 
the  loop  after  the  experiment  is  less  than  the  amount  of 
purgative  solution  left.  If  the  quantities  of  the  two  salts 
were  equal  in  the  beginning  and  an  equal  amount  were  ab- 
sorbed, there  would  still  be  more  fluid  left  in  the  loop  con- 
taining the  purgative  on  account  of  the  secretion  of  fluid 
into  the  loop  which  was  caused  by  the  purgative,  and  not  by 
the  NaCl. 

With  regard  to  the  mode  in  which  the  salt  must  be  ad- 
ministered it  is  quite  clear  that  it  is  not  necessary  to  place 
it  in  the  stomach  or  the  lumen  of  the  intestine.  As  shown 
above,  the  action  is  more  rapid  and  more  powerful  when 
the  solution  is  injected  into  the  blood,  or  applied  locally  to 
the  peritoneal  surface  of  the  intestine.     Nor  is  the  action 


79 


due  to  its  being  secreted  again  into  the  lumen  of  the  intes- 
tine, because  the  action  is  almost  immediate  when  the  solu- 
tion is  poured  on  the  outside  of  the  loops,  and  only  takes 
place  after  several  minutes  when  placed  in  the  lumen.  If 
injected  into  the  blood  the  action  is  slov/er  than  when  the 
solution  is  applied  to  the  serous  surfaces  of  the  intestine. 
In  the  former  case  every  opportunity  would  be  afforded  for 
its  rapid  excretion  into  the  intestine  if  that  were  a  factor. 
It  is  evident  that  the  solution  must  be  absorbed  into  the 
blood  and  bathe  the  tissues  just  as  a  solution  surrounds  a 
muscle  which  is  immersed  in  it. 

As  to  the  tissues  in  the  intestine  which  are  primarily 
affected,  it  is  impossible  to  make  a  definite  statement.  The 
muscle  and  glands  cannot  be  at  all  separated  from  the  com- 
plex nervous  mechanism  of  the  intestine,  and  it  is  necessary 
to  take  the  whole  as  an  organ  made  up  of  many  tissues  and 
affected  in  definite  ways  by  certain  solutions. 

It  is  interesting  in  this  connection  to  again  note  the 
effect  of  these  salts  on  the  secretion  of  urine.  It  is  well 
known  that  practically  all  of  them  are  diuretics,  when  intro- 
duced with  a  considerable  amount  of  fluid.  And  even  when 
the  flow  of  urine  has  been  greatly  increased  by  the  injection 
of  m/6  NaCl  solution,  it  can  be  still  further  augmented  by 
the  addition  of,  e.g.,  sodium  citrate  to  the  injection  fluid. 
These  salts  constitute  the  well  known  class  of  saline  diu- 
retics. All  salts  do  not,  however,  belong  to  this  class,  as  is 
often  stated.  Calcium  chloride,  magnesium  chloride,  and 
to  some  extent  strontium  chloride  exert  exactly  the  oppo- 
site effect,  inhibiting  the  action  of  the  diuretics  and  dimin- 
ishing the  flow  of  urine.  These  salts  might  be  termed  anti- 
diuretics. There  is  thus  an  entire  analogy  between  the  ac- 
tion of  the  saline  diuretics  on  the  kidney  and  that  of  the 
saline  purgatives  on  the  intestine,  and  also  the  action  of 
calcium  and  magnesium  is  the  same  in  both  cases.  And  the 
analogy  can  be  traced  farther  back  to  the  production  and 
inhibition  of  muscular  twitchings  in  voluntary  muscles, 
which  was  demonstrated  by  Loeb. 


80 

The  actual  mechanism  of  the  secretion  of  fluid  into  the 
intestine  is  difficult  to  determine.  It  seems  improbable  that 
a  change  in  blood  pressure  plays  any  very  important  role, 
if  indeed  it  has  an  influence  at  all.  There  is  much  evidence 
to  show  that  many  glands  consisting  of  cells  resembling 
those  of  the  intestine  roughly,  secrete  their  characteristic 
fluids  quite  independently  of  blood  pressure.  In  Sida  crys- 
tallina,  a  small  fresh-water  crustacean,  it  was  found^®  that 
if  a  small  quantity  of  one  of  the  saline  purgatives  or  of 
BaCl,  or  pilocarpine  be  added  to  the  water  in  which  these 
crustaceans  are  lying,  there  is  not  only  a  rapid  increase  of 
intestinal  movement  and  a  rapid  evacuation  of  faeces,  but 
there  is  also  an  increased  secretion  of  fluid  into  the  intes- 
tine, so  that  the  whole  lumen  becomes  filled  with  a  pale 
greenish  fluid.  It  was  pointed  out  further  that  in  this  or- 
ganism there  is  no  closed  blood  vascular  system,  the  blood 
simply  running  in  wide  channels  in  more  or  less  definite 
directions.  There  can  therefore  exist  nothing  here  com- 
parable with  the  blood  pressure  of  higher  animals,  and  yet 
secretion  normally  takes  place  without  changes  in  blood 
pressure.  Further,  it  can  be  greatly  increased  by  chemi- 
cals without  an  increase  in  blood  pressure  being  possible. 
A  similar  secretion  without  blood  pressure  as  a  causative 
factor  is  seen  in  the  skin  of  the  common  slug  (Ariolimax). 
Here  the  secretion  of  the  skin  may  be  markedly  increased 
by  the  injection  or  local  application  of  a  solution  of  any  of 
the  saline  purgatives.  This  takes  place  equally  well  when 
the  heart  of  the  animal  is  removed,  and  also  in  an  isolated 
portion  of  the  animal,  or  in  a  piece  of  the  skin  cut  off  with 
the  scissors.  In  these  latter  cases  there  can  be  no  possi- 
bility of  blood  pressure  taking  a  part  in  the  secretion. 

It  has  been  further  shown®''  that  loops  of  intestine  en- 
tirely removed  from  the  body  may  be  caused  to  secrete  a 

^^  MacCallum,  J.  B. :  University  of  California  Publications,  Phys- 
iology, Vol.  II,  1905,  p.  65. 

^^  MacCallum,  J.  B. :  University  of  California  Publications,  Phys- 
iology, Vol.  I,  1904,  p.  115. 


81 


measurable  quantity  of  fluid  by  immersing  them  in  certain 
purgative  solutions,  especially  those  containing  BaCL. 
Other  solutions  such  as  pure  m/6  NaCl  do  not  cause  this 
secretion,  although  active  peristaltic  movements  go  on  in 
NaCl.  In  this  case  the  secretion  must  be  entirely  independ- 
ent of  the  blood  pressure.  Pilocarpine  also  in  the  salivary 
gland  causes  an  enormous  increase  in  the  secretion,  without 
raising  the  blood  pressure  in  the  carotid. 

It  is  certain  from  these  facts  that  in  many  glands  secre- 
tion is  quite  independent  of  any  change  in  blood  pressure; 
and  it  seems  probable  that  such  changes  must  play  a  very 
subordinate  part  in  the  secretion  of  fluid  from  the  intestine. 

On  the  other  hand,  it  is  to  be  noted  that  in  many  in- 
stances muscular  and  secretory  activities  are  controlled  by 
the  same  conditions.  There  seems  to  be  a  common  factor 
in  the  production  of  the  two  functions.  Saline  purgatives 
produce  not  only  muscular  activity,  but  also  increased  se- 
cretion; and  calcium  and  magnesium  are  capable  of  inhib- 
iting both.  Atropin  also  quiets  the  movements  of  the  in- 
testine, and  at  the  same  time  is  conspicuous  in  suppressing 
the  secretion.  Section  of  the  splanchnic  nerves  causes  not 
only  increased  muscular  movements,  but  an  increased  secre- 
tion of  fluid  in  the  intestine.  These  instances  could  be 
greatly  increased  in  number.  From  them  it  seems  that 
something  exists  in  common  in  muscular  movements  and  in 
glandular  activity.  What  first  suggests  itself  is  that  the 
gland  cells  themselves  are  made  to  contract  rhythmically 
by  the  various  conditions  which  cause  rhythmical  contrac- 
tions in  muscle.  That  the  stimulus  for  this  must  be  greater 
in  the  case  of  secretion  is  shown  by  the  fact  that  in  the  in- 
testine peristaltic  movements  may  be  maintained  in  a  solu- 
tion (m/6  NaCl)  in  which  no  secretion  takes  place.  It 
seems  not  at  all  improbable  that  one  factor  in  the  produc- 
tion of  secretory  activity  is  dependent  on  a  property  of  the 
gland  cell  closely  related  to  muscular  contractility. 


82 


A  further  factor  is  suggested  by  the  action  of  •  certain 
diuretics.  In  the  kidney  the  changes  in  the  quantity  of 
blood  flowing  through  the  organ  and  to  some  extent  changes 
in  blood  pressure  influence  the  flow  of  urine.  The  diuresis 
produced  by  such  substances,  however,  as  saponin,  digita- 
lin,  potassium  chlorate,  etc.,  probably  depends  on  an  in- 
crease in  permeability  of  the  capsule  of  BoM-man.  As 
shown^°  recently,  these  substances  produce  haemolysis,  and 
are  also  strong  diuretics.  Calcium  chloride,  which  inhibits 
the  flow  of  urine  produced  by  them,  inhibits  also  the  hae- 
molysis. Haemoglobinuria,  which  readily  appears  with 
small  doses  of  saponin  or  digitalin,  is  inhibited  by  simulta- 
neously injecting  calcium  chloride.  There  thus  seems  to  be 
something  in  common  between  haemolysis  and  diuresis ;  and 
what  suggests  itself  as  most  probable  is  that  the  permea- 
bility of  the  red  blood  corpuscle,  as  well  as  that  of  the  kid- 
ney cell  is  increased,  so  that  on  the  one  hand  haemoglobin 
escapes  into  the  blood  (is  secreted  into  the  blood),  and  the 
amount  of  urine  on  the  other  hand  passing  through  the 
kidney  cell  is  increased.  Calcium,  according  to  the  same 
idea,  would  decrease  the  permeability  in  both  cases. 

In  secretion  we  have  therefore  among  other  things  two 
factors  which  probably  play  a  role,  namely,  a  property  of 
the  gland  cell  resembling  that  of  muscular  contractility  and 
controlled  in  many  cases  by  the  same  conditions,  and  a 
change  in  permeability  of  the  cells  which  are  secreting.  In 
the  kidney  there  is  a  third  factor  dependent  on  the  flow  of 
blood  through  the  organ.  A  continuous  supply  of  blood  is 
of  course  necessary  in  all  glands  for  a  continued  secretion. 


°°  MacCallum,  J.  B. :  University  of  California  Publications,  Phys- 
iology, Vol.  II,  1905,  p.  93. 


CHAPTEE  X. 
Possible  Therapeutic  Value  of  These  Experiments. 

It  at  once  suggests  itself  to  the  physician  that  some  clin- 
ical use  might  be  made  of  the  facts  outlined  above.  If  such 
striking  results  can  be  obtained  in  a  rabbit  it  is  possible  that 
some  modifications  of  the  use  of  these  saline  purgatives 
might  be  made  in  the  human  being. 

If  in  the  first  place  it  is  found  that  subcutaneous  or  in- 
travenous injections  of  saline  purgatives  are  effective  in 
man,  there  arise  in  both  medical  and  surgical  practice  oc- 
casions in  which  these  methods  of  administration  would  be 
of  the  greatest  advantage.  It  is  to  be  remembered  in  this 
connection  that  the  administration  by  these  methods  of 
MgS04  is  especially  dangerous.  This  salt  when  rapidly  ab- 
sorbed seems  to  be  very  poisonous.  Rabbits  frequently  die 
in  a  few  minutes  after  an  intravenous  injection  of  a  quan- 
tity relatively  small  as  compared  with  the  amount  of  Nag 
SO4  which  can  be  given  in  this  way.  Barium  chloride  is 
extremely  active  as  a  subcutaneous  purgative,  but  should  be 
used  with  the  greatest  caution  and  in  very  minute  quanti- 
ties on  account  of  its  very  poisonous  character.  I  can  give 
no  idea  of  the  dose  that  might  be  given  to  a  human  being 
without  danger.  A  rabbit  usually  does  not  recover  from  a 
subcutaneous  injection  of  3  c.c.  m/8  BaCl  solution. 

The  fact  that  saline  purgative  solutions  applied  to  the 
peritoneal  surfaces  of  the  intestine  act  very  rapidly  may 
suggest  some  use  in  abdominal  surgery  for  this  method.  If 
it  were  desirable  to  have  evacuation  of  the  bowel  rapidly 


84 


follow  an  abdominal  operation  this  procedure  might  be  re- 
sorted to.  An  isotonic  solution  (m/6)  of  sodium  sulphate 
or  sodium  citrate  would  be  most  favorable  for  this  purpose. 

The  possible  uses  to  which  our  knowledge  of  the  action 
of  calcium  may  be  put  has  aroused  some  discussion.  The 
fact  that  it  suppresses  muscular  and  nervous  irritability 
(Loeb),  and  as  shown  in  the  experiments  above,  inhibits  the 
muscular  and  glandular  activity  of  the  intestine,  as  well  as 
the  secretory  activity  of  the  kidney,  makes  it  seem  probable 
that  some  practical  use  may  be  made  of  it  in  certain  condi- 
tions in  the  human  being.  The  most  important  of  these 
conditions  is  perhaps  the  persistent  diarrhoea  which  some- 
times accompanies  disorders  of  an  hysterical  or  neuras- 
thenic sort.  There  have  already  come  under  my  notice  sev- 
eral cases  of  diarrhcea  of  nervous  origin  which  were  quite 
uncontrolled  by  morphine  preparations.  These  cases  were 
apparently  entirely  relieved  by  calcium  chloride  given  for 
only  a  few  days,  (grs  XX  t.i.d.)  Whether  a  large  number 
of  similar  patients  will  show  the  same  results  remains  to  be 
seen.  The  treatment  is  evidently  to  be  applied  to  only  a 
small  class  of  patients,  roughly  those  cases  of  persistent 
diarrhoja  of  apparently  nervous  origin,  which  cannot  be 
influenced  by  opiates. 

When  rectal  infusions  of  NaCl  are  not  retained  it  is 
possible  by  adding  CaCL  to  the  solution  to  stop  the  move- 
ments of  the  rectum  which  cause  their  expulsion.  Enemata 
of  NaCl  containing  CaClg  are  retained  much  better  than 
those  of  pure  NaCl. 

The  marked  action  of  calcium  on  the  kidney  suggests 
that  certain  conditions  might  arise  where  it  could  be  made 
use  of.  In  nervous  polyuria  it  can  be  given  with  benefit ; 
and  although  we  know  practically  nothing  as  to  the  etiology 
of  diabetes  insipidus,  it  is  possible  that  calcium  might  be 
employed  with  advantage  to  stop  the  abnormal  flow  of 
urine. 

With  regard  to  general  conditions  such  as  the  muscular 


85 


and  nervous  irritability  accompanying  hysterical  and  neu- 
raesthenic  disturbances  little  can  be  said  as  to  the  possible 
value  of  calcium.  Loeb  drew  attention  to  the  possibilities 
of  its  being  of  use  in  these  diseases,  but  there  is  not  suffi- 
cient evidence  to  make  any  statement  concerning  it.  The 
extreme  irritability  which  is  present  in  some  types  of  in- 
sanity might  also  be  tested  in  this  respect. 

Calcium  might  also  be  of  benefit  in  asthma  where  the 
two  distressing  symptoms  are  spasmodic  contractions  of  the 
bronchioles  and  a  hypersecretion  from  the  mucous  mem- 
brane of  the  larger  and  smaller  bronchi.  Judging  by  anal- 
ogy from  the  experiments  described  above,  calcium  should 
not  only  relieve  the  muscular  contractions  but  also  inhibit 
the  secretion. 

These  suggestions  are  made  simply  in  the  hope  of  stim- 
ulating clinical  research  in  this  direction. 

Wright  has  recently  stated  that  calcium  relieves  urti- 
caria, a  circumstance  which  he  refers  to  the  influence  of 
calcium  on  the  coagulability  of  the  blood,  which  he  says  is 
diminished  in  this  condition.  It  seems  more  probable  from 
the  above  experiments  that  the  calcium  inhibits  the  secre- 
tion or  passage  of  fluid  from  the  lymph  vessels  to  form  the 
vesicles. 


CHAPTER  XI. 
The  Action  of  Purgatives  of  Vegetable  Origin. 

This  group  of  purgatives,  as  far  as  its  general  properties 
are  concerned,  is  so  well  described  in  many  text-books  that 
it  is  unnecessary  here  to  go  into  the  details  of  their  prepa- 
ration and  the  commoner  characteristics  of  each.  Certain 
points  which  have  come  up  in  connection  with  my  own  ex- 
periments, however,  may  be  briefly  described  here. 

Cascara  Sagrada  is  prepared  in  many  ways,  but  the 
most  favorable  preparation  for  experiment  is  the  dried  ex- 
tract. This  is  the  dark  yellow  powder  familiar  in  com- 
merce. It  is  found  that  in  shaking  this  powder  in  distilled 
water  it  is  almost  entirely  insoluble.  The  result  is  a  dirty 
yellow  mixture,  the  filtrate  from  which  gives  an  acid  reac- 
tion. This  suggested  neutralizing  the  mixture  or  making 
it  alkaline.  A  small  amount  of  sodium  bicarbonate  was 
added,  and  the  powder  immediately  went  into  solution,  pro- 
ducing a  clear  dark  brown  fluid.^^  A  similar  result  was 
obtained  by  adding  sodium  hydrate.  It  was  found  that  % 
g.  of  the  dried  extract  could  be  dissolved  in  25  c.c.  m/24 
NaHCOg.  This  solution  in  NaHCOg  is  practically  neutral. 
If  a  few  drops  of  dilute  HoSO^  be  added  a  yellow  precipi- 
tate at  once  appears  giving  a  mixture  or  suspension  similar 
to  that  originally  obtained  by  adding  the  powder  to  distilled 
water.  The  addition  of  NaHCOg  will  again  produce  the 
characteristic  dark  brown  solution.  The  extract  is  much 
more  readily  soluble  in  a  stronger  solution  of  NaHCOg. 

°^  MacCallum,  J.  B. :  University  of  California  Publications,  Phys- 
iology, Vol.  I,  p.  163. 


87 


The  dried  extract  is  thus  soluble  only  in  a  neutral  or 
alkaline  fluid.  It  is  insoluble  in  distilled  water  on  account 
of  the  free  acid  which  is  present  in  the  powder. 

Cascara  extract  is  readily  soluble  in  the  intestinal  juice 
of  a  rabbit,  a  characteristic  dark  brown  clear  solution  being 
obtained.  On  the  other  hand,  it  is  insoluble  in  the  gastric 
juice,  and  an  alkaline  solution  added  to  the  gastric  juice  is 
at  once  precipitated. 

It  was  found  that  the  intravenous  injection  of  1  c.c.  of 
a  2%  solution  of  cascara  extract  in  m/25  NaHCOg  pro- 
duces within  a  minute  very  strong  peristaltic  movements  in 
the  intestine.  A  similar  injection  of  the  same  amount  of 
m/25  NaHCOg  alone  produces  no  such  result,  though 
stronger  solutions  of  NaHCOg  cause  a  slight  increase  in  in- 
testinal movements.  It  is  therefore  the  cascara  in  solution 
which  produces  these  strong  contractions. 

A  somewhat  larger  quantity  of  the  cascara  solution  in- 
jected subeutaneously  produces  increased  peristaltic  activ- 
ity after  an  interval  of  several  minutes. 

If  the  cascara  solution  be  applied  directly  to  the  serous 
surfaces  of  the  intestine,  very  strong  contractions  and  peri- 
staltic movements  result  in  2  or  3  minutes.  A  solution  of 
m/25  NaHCO,  alone  produces  very  slight  movements  when 
applied  in  this  way.  These  can,  however,  be  readily  distin- 
guished from  those  produced  by  cascara.  The  latter  are 
much  more  powerful,  are  slower  in  developing,  and  can  be 
only  partially  inhibited  by  m/6  CaCL-  The  movements  fol- 
lowing the  application  of  pure  NaHCOg  solution,  however, 
are  weak,  they  appear  almost  immediately,  and  can  be  en- 
tirely suppressed  by  the  application  of  m/6  CaCla  solution. 

When  the  cascara  solution  is  placed  in  the  stomach  no 
movements  appear  in  the  intestine  even  after  15-30  min- 
utes. The  acid  of  the  gastric  juice  has  evidently  precipi- 
tated the  cascara,  which  cannot  act  until  it  is  passed  on 
into  the  intestine  where  it  may  be  dissolved  in  the  alkaline 
juice  of  the  intestine.    If  instead  of  placing  the  solution  in 


the  stomach  it  is  injected  directly  into  the  small  intestine, 
increased  peristaltic  movements  begin  within  "5  minutes. 
Here  it  evidently  remains  in  solution  and  is  absorbed.  It 
is  for  this  reason  that  in  human  beings  cascara  taken  ,by 
mouth  acts  only  after  several  hours.  It  is  precipitated  in 
the  stomach  and  must  reach  the  intestine  before  it  is 'dis- 
solved and  absorbed. 

In  addition  to  the  increased  peristaltic  activity  caused 
by  the  cascara,  there  seems  to  be  also  an  increase  in  the 
secretion  of  fluid  into  the  lumen.  One  or  two  hours  after 
the  injection  20-30  c.c.  fluid  could  be  collected  from  the 
small  intestine.  Without  the  purgative  it  is  rarely  possible 
to  obtain  more  than  5  to  10  c.c. 

It  was  found  that  calcium  chloride  has  only  a  very 
transient  effect  in  inhibiting  the  increased  movements  pro- 
duced by  cascara.  For  2  or  3  minutes  following  the  injec- 
tion of  CaClg  the  movements  were  usually  quieted,  but  they 
rapidly  began  again  and  continued  as  vigorously  as  before. 

The  behavior  of  rhubarb  is  in  every  way  similar  to  that 
of  cascara.  It  is  less  readily  soluble,  but  the  solution  acts 
in  a  way  quite  like  that  described  for  cascara. 

It  is  further  well  known  that  aloin  injected  subcuta- 
neously  causes  increased  peristalsis.  A  study  has  recently 
been  made  of  certain  constituents  of  the  derivatives  of  the 
aloes  group  of  purgatives.  Esselmont,''^  following  the  work 
of  Tschirch,^*  experimented  with  a  number  of  substances 
obtained  from  these  purgatives.  Aloeemodin  is  present 
not  only  in  aloes,  but  also  in  Cascara  sagrada  and  senna 
leaves.  A  small  amount  of  this  substance  acts  as  a  purga- 
tive. Alochrysin,  aloingrin,  barbaloin,  all  act  as  purgatives. 
Chrysophanic  acid,  which  is  found  in  aloes,  rhubarb,  and 
senna  is  a  mild  purgative.  It  is  of  interest  to  note  that 
each  of  these  substances  is  either  a  di-  or  tri-oxymethylan- 
thrachinon.    They  owe  their  purgative  action,  according  to 

»^  Archiv  f .  exp.  Path.  u.  Pharm.,  Bd.  43,  1900,  S.  274. 

^  Schweiz.  Wochenschrift  fiir  Chemie  und  Pharmacie,  1898,  No.  23. 


Tschireh,  to  their  containing  the  oxymethylanthrachinon 
group. 

Some  experiments^^  which  I  recently  made  on  a  jelly- 
fish (Polyorchis)  with  some  of  the  vegetable  purgatives  are 
of  interest.  They  were  suggested  by  the  experiments  of 
Loeb^*'  on  the  effect  of  various  salts  on  the  isolated  center 
of  the  animal  and  of  a  related  form  (Gonionemus).  When 
separated  from  the  margins  the  bell-like  centers  of  these 
jellyfish  do  not  beat  in  pure  sea-water.  In  case  of  Gonio- 
nemus it  was  found  that  the  addition  of  one  of  a  number  of 
salts  (calcium  precipitants)  caused  the  center  to  beat.  This 
group  of  salts  includes  the  so-called  saline  purgatives. 

The  methods  used  in  the  experiments  with  vegetable 
purgatives  were  practically  the  same  as  those  used  by  Loeb. 
The  animal  was  bisected  just  above  the  ring  of  sense  organs 
in  order  to  entirely  remove  the  margin  containing  the  main 
nervous  system.  The  center  was  then  placed  in  mixtures 
of  sea-water  and  solutions  of  the  purgatives.  The  center 
never  beats  in  pure  sea-water,  but  was  found  to  beat  vigor- 
ously in  sea-water  to  which  a  small  quantity  of  a  solution 
of  cascara,  rhubarb,  aloin,  podophyllin,  or  colocynth  had 
been  added.  It  was  necessary  to  dissolve  the  cascara  and 
rhubarb  extracts  in  m/24  NaHCOg,  since  they  are  not  sol- 
uble in  pure  water.  The  centers  do  not  beat  in  sea-water 
to  which  pure  m/24  NaHCOg  has  been  added  in  quantities 
equivalent  to  those  added  with  the  purgative  solution. 

A  solution  of  i^  g.  cascara  extract  was  made  in  50  c.c. 
m/24  NaHCOg.  It  was  found  that  a  mixture  of  25  c.c.  sea- 
water  -|-  2  c.c.  of  this  cascara  solution  was  the  most  favor- 
able for  producing  rhythmical  contractions  in  the  isolated 
center  of  Polyorchis.    Contractions  lasted  10-15  minutes. 

A  solution  of  rhubarb  extract  of  the  same  strength  was 
made.  The  optimal  mixture  in  this  case  is  25  c.c.  sea-water 
-f-  0.5  c.c.  or  1  c.c.  rhubarb  solution.  In  this  mixture  the 
contractions  develop  quickly  and  last  15  minutes  or  more. 

°°  To  appear  shortly  in  Journal  of  Biological  Chemistry. 
^^  Loc.  cit. 


90 


With  aloin  the  concentration  of  the  purgative  needed  to 
produce  optimal  results  was  somewhat  greater  than  in  cas- 
cara  or  rhubarb.  Colocynth  and  podophyllin  act  similarly, 
but  the  contractions  soon  cease.  ^ 

These  vegetable  purgatives  thus  act  on  the  jellyfish, 
Polyorchis,  in  a  way  quite  similar  to  that  described  by  Loeb 
for  saline  purgatives. 

Pilocarpine,  though  not  used  as  a  purgative  on  account 
of  its  special  action  on  other  organs  of  the  body,  has  a  pow- 
erful action  also  on  the  intestine.  Its  influence  on  the  in- 
testine is  much  like  that  of  barium  chloride.  It  causes  vio- 
lent contractions  of  the  musculature  of  the  gut  and  very 
active  peristaltic  movements.  This  is  the  case  in  whatever 
way  the  substance  is  administered.  A  few  drops  of  a  1/10% 
solution  of  pilocarpine  hydrochlorate  in  distilled  water 
poured  on  the  serous  surfaces  of  the  rabbit's  intestine 
brings  about  almost  immediately  violent  peristaltic  move- 
ments. In  addition  to  this  there  is  an  increase  in  the 
amount  of  fluid  secreted  into  the  intestine,  20-30  c.c.  gath- 
ering in  the  small  intestine  in  an  hour.  The  evacuation  of 
faeces  takes  place  in  about  three-quarters  of  an  hour.  These 
may  be  of  a  semifluid  character,  and  with  larger  doses  re- 
semble the  faeces  produced  by  BaClg.  The  antagonism  be- 
tween pilocarpine  and  CaClg  is  incomplete.  CaClg  is  capa- 
ble of  inhibiting  only  temporarily  the  movements  caused  by 
pilocarpine. 

It  is  interesting  to  note  the  marked  purgative  effect  of 
pilocarpine  in  a  small  fresh-water  crustacean  (Sida  crystal- 
Una).  This  animal,  which  has  been  spoken  of  in  previous 
chapters  belongs  to  the  Cladocera.  The  intestine  extends 
in  a  fairly  straight  line  throughout  the  body,  bending  down- 
ward at  the  post  abdomen  to  open  to  the  outside.  At  the 
anterior  end  is  a  slight  dilatation  which  may  represent  the 
stomach.  From  this  there  open  two  diverticula  or  coeca 
which  seem  to  be  of  a  glandular  nature,  and  are  sometimes 
spoken  of  as  digestive  glands.    They  are  usually  filled  with 


91 


a  greenish  fluid.  The  intestine  is  always  filled  with  brown 
faeces  which  are  normally  expelled  in  small  quantities,  only 
at  considerable  intervals.  Slight  peristaltic  waves  are  com- 
monly seen  in  the  lower  part  of  the  intestine. 

These  animals  were  placed  in  various  solutions,  and  it 
was  found^^  that  pilocarpine  hydrochlorate,  aloin,  eascara, 
as  well  as  barium  chloride,  sodium  citrate,  sulphate,  and 
fluoride,  caused  an  increased  peristaltic  activity  of  the  in- 
testine, and  a  rapid  expulsion  of  faeces,  so  that  in  a  very 
short  time  the  entire  intestine  was  empty.  At  the  same 
time  the  intestine  becomes  filled  with  a  greenish  fluid  sim- 
ilar to  that  seen  in  the  diverticula.  This  fluid  may  be  also 
expelled  and  replaced  again.  It  is  evidently  secreted  by 
the  intestine  or  by  the  diverticula  as  a  result  of  the  purga- 
tive action.  Very  dilute  solutions  of  pilocarpine  are  suffi- 
cient to  bring  about  this  effect.  In  a  1%  solution  the  action 
is  very  rapid,  and  evacuation  of  faeces  may  be  brought 
about  by  a  mixture  of  1  c.c.  0.1%  pilocarpine  in  10  c.c. 
water.    This  takes  place  within  20  minutes. 

An  attempt  was  made  to  determine  whether  or  not  CaCla 
is  capable  of  inhibiting  the  action  of  pilocarpine..  The  ex- 
periments on  rabbits  in  this  respect  were  unsatisfactory.  It 
was  found  that  the  greatest  dilution  at  which  expulsion  of 
faeces  in  Sida  could  be  caused  in  a  short  period  of  time 
was  1  c.c.  0.1%  pilocarpine  -|-  10  c.c.  water.  Animals  were 
placed  in  a  mixture  of  1  c.c.  0.1%  pilocarpine  -|-  10  c.c. 
m/6  CaCla-  These  behaved  exactly  as  though  the  water  had 
not  been  replaced  by  CaCL.  In  other  words,  the  presence 
of  the  CaCla  did  not  delay  at  all  the  action  of  the  pilocar- 
pine. This  was  repeated  many  times,  and  it  seems  that  in 
Sida  at  least  the  action  of  pilocarpine  is  not  at  all  antag- 
onized by  calcium  chloride.  In  a  mixture,  however,  of  10 
c.c.  1%  atropin  sulphate  -f- 1  c.c.  0.1%  pilocarpine  no  evac- 
uation of  faeces  took  place  and  there  was  no  increase  in 
peristalsis. 

■"  MacCallum,  J.  B. :  University  of  California  Publications,  Vol. 
II,  1905,  p.  65. 


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